The evolution of costly acquired immune memory

A key feature of the vertebrate adaptive immune system is acquired immune memory, whereby hosts launch a faster and heightened response when challenged by previously encountered pathogens, preventing full infection. Here, we use a mathematical model to explore the role of ecological and epidemiological processes in shaping selection for costly acquired immune memory. Applying the framework of adaptive dynamics to the classic SIR (Susceptible-Infected-Recovered) epidemiological model, we focus on the conditions that may lead hosts to evolve high levels of immunity. Linking our work to previous theory, we show how investment in immune memory may be greatest at long or intermediate host lifespans depending on whether immunity is long lasting. High initial costs to gain immunity are also found to be essential for a highly effective immune memory. We also find that high disease infectivity and sterility, but intermediate virulence and immune period, increase selection for immunity. Diversity in host populations through evolutionary branching is found to be possible but only for a limited range of parameter space. Our model suggests that specific ecological and epidemiological conditions have to be met for acquired immune memory to evolve

The paradox of tolerance: parasite extinction due to the evolution of host defence.

Host defence against parasite infection can rely on two broad strategies: resistance and tolerance. The spread of resistance traits usually lowers parasite prevalence and decreases selection for higher defence. Conversely, tolerance mechanisms increase parasite prevalence and foster selection for more tolerance. Here we examine the potential for the host to drive parasites to extinction through the evolution of one or other defence mechanism. We analysed theoretical models of resistance and tolerance evolution in both the absence and the presence of a trade-off between defence and reproduction. In the absence of costs, resistance evolves towards maximisation and, consequently, parasite extinction. Tolerance also evolves towards maximisation but the positive feedback between tolerance and disease prevents the disappearance of the parasite. On the contrary, when defence comes with costs it is impossible for the host to eliminate the infection through resistance, because costly resistance is selected against when parasites are at low prevalence. We uncover that the only path to disease clearance in the presence of costs is through tolerance. Paradoxically, however, it is by lowering tolerance -and hence increasing disease-induced mortality- that extinction can occur. We also show that such extinction can occur even in the case of parasite counter-adaptation. Our results emphasise the importance of tolerance as a defence strategy, and identify key questions for future research

Accumulation of copy number alterations and clinical progression across advanced prostate cancer

Background: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown. Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression. Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10−6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037). Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes

Galaxy Zoo: Chiral correlation function of galaxy spins

Galaxy Zoo is the first study of nearby galaxies that contains reliable information about the spiral sense of rotation of galaxy arms for a sizeable number of galaxies. We measure the correlation function of spin chirality (the sense in which galaxies appear to be spinning) of face-on spiral galaxies in angular, real and projected spaces. Our results indicate a hint of positive correlation at separations less than ~0.5 Mpc at a statistical significance of 2-3 sigma. This is the first experimental evidence for chiral correlation of spins. Within tidal torque theory it indicates that the inertia tensors of nearby galaxies are correlated. This is complementary to the studies of nearby spin axis correlations that probe the correlations of the tidal field. Theoretical interpretation is made difficult by the small distances at which the correlations are detected, implying that substructure might play a significant role, and our necessary selection of face-on spiral galaxies, rather than a general volume-limited sample.Comment: 9 pages, 5 figures; v2: minor changes, matches version accepted by MNRA

Galaxy Zoo: A correlation between coherence of galaxy spin chirality and star formation efficiency

We report on the finding of a correlation between galaxies' past star formation activity and the degree to which neighbouring galaxies rotation axes are aligned. This is obtained by cross-correlating star formation histories, derived with MOPED, and spin direction (chirality), as determined by the Galaxy Zoo project, for a sample of SDSS galaxies. Our findings suggest that spiral galaxies which formed the majority of their stars early (z > 2) tend to display coherent rotation over scales of ~10 Mpc/h. The correlation is weaker for galaxies with significant recent star formation. We find evidence for this alignment at more than the 5-sigma level, but no correlation with other galaxy stellar properties. This finding can be explained within the context of hierarchical tidal-torque theory if the SDSS galaxies harboring the majority of the old stellar population where formed in the past, in the same filament and at about the same time. Galaxies with significant recent star formation instead are in the field, thus influenced by the general tidal field that will align them in random directions or had a recent merger which would promote star formation, but deviate the spin direction.Comment: matches published version in MNRAS; only minor change

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment