Integrative DNA methylome analysis of pan-cancer biomarkers in cancer discordant monozygotic twin-pairs

BACKGROUND: A key focus in cancer research is the discovery of biomarkers that accurately diagnose early lesions in non-invasive tissues. Several studies have identified malignancy-associated DNA methylation changes in blood, yet no general cancer biomarker has been identified to date. Here, we explore the potential of blood DNA methylation as a biomarker of pan-cancer (cancer of multiple different origins) in 41 female cancer discordant monozygotic (MZ) twin-pairs sampled before or after diagnosis using the Illumina HumanMethylation450 BeadChip. RESULTS: We analysed epigenome-wide DNA methylation profiles in 41 cancer discordant MZ twin-pairs with affected individuals diagnosed with tumours at different single primary sites: the breast, cervix, colon, endometrium, thyroid gland, skin (melanoma), ovary, and pancreas. No significant global differences in whole blood DNA methylation profiles were observed. Epigenome-wide analyses identified one novel pan-cancer differentially methylated position at false discovery rate (FDR) threshold of 10 % (cg02444695, P = 1.8 × 10(-7)) in an intergenic region 70 kb upstream of the SASH1 tumour suppressor gene, and three suggestive signals in COL11A2, AXL, and LINC00340. Replication of the four top-ranked signals in an independent sample of nine cancer-discordant MZ twin-pairs showed a similar direction of association at COL11A2, AXL, and LINC00340, and significantly greater methylation discordance at AXL compared to 480 healthy concordant MZ twin-pairs. The effects at cg02444695 (near SASH1), COL11A2, and LINC00340 were the most promising in biomarker potential because the DNA methylation differences were found to pre-exist in samples obtained prior to diagnosis and were limited to a 5-year period before diagnosis. Gene expression follow-up at the top-ranked signals in 283 healthy individuals showed correlation between blood methylation and gene expression in lymphoblastoid cell lines at PRL, and in the skin tissue at AXL. A significant enrichment of differential DNA methylation was observed in enhancer regions (P = 0.03). CONCLUSIONS: We identified DNA methylation signatures in blood associated with pan-cancer, at or near SASH1, COL11A2, AXL, and LINC00340. Three of these signals were present up to 5 years prior to cancer diagnosis, highlighting the potential clinical utility of whole blood DNA methylation analysis in cancer surveillance

Inexact Bayesian point pattern matching for linear transformations

PublishedArticleWe introduce a novel Bayesian inexact point pattern matching model that assumes that a linear transformation relates the two sets of points. The matching problem is inexact due to the lack of one-to-one correspondence between the point sets and the presence of noise. The algorithm is itself inexact; we use variational Bayesian approximation to estimate the posterior distributions in the face of a problematic evidence term. The method turns out to be similar in structure to the iterative closest point algorithm.This work was supported by the University of Exeter’s Bridging the Gaps initiative, which was funded by EPSRC award EP/I001433/1 and the collaboration was formed through the Exeter Imaging Network

Validating a methodology to measure frailty syndromes at hospital level utilising administrative data.

BACKGROUND: Identifying older people with clinical frailty, reliably and at scale, is a research priority. We measured frailty in older people using a novel methodology coding frailty syndromes on routinely collected administrative data, developed on a national English secondary care population, and explored its performance of predicting inpatient mortality and long length of stay at a single acute hospital. METHODOLOGY: We included patient spells from Secondary User Service (SUS) data for those ≥65 years with attendance to the emergency department or admission to West Middlesex University Hospital between 01 July 2016 to 01 July 2017. We created eight groups of frailty syndromes using diagnostic coding groups. We used descriptive statistics and logistic regression to explore performance of diagnostic coding groups for the above outcomes. RESULTS: We included 17,199 patient episodes in the analysis. There was at least one frailty syndrome present in 7,004 (40.7%) patient episodes. The resultant model had moderate discrimination for inpatient mortality (area under the receiver operating characteristic curve (AUC) 0.74; 95% confidence interval (CI) 0.72-0.76) and upper quartile length of stay (AUC 0.731; 95% CI 0.722-0.741). There was good negative predictive value for inpatient mortality (98.1%). CONCLUSIONS: Coded frailty syndromes significantly predict outcomes. Model diagnostics suggest the model could be used for screening of elderly patients to optimise their care

Segmental identity and cerebellar granule cell induction in rhombomere 1

BACKGROUND: Cerebellar granule cell precursors are specifically generated within the hindbrain segment, rhombomere 1, which is bounded rostrally by the midbrain/hindbrain isthmus and caudally by the boundary of the Hoxa2 expression domain. While graded signals from the isthmus have a demonstrable patterning role within this region, the significance of segmental identity for neuronal specification within rhombomere 1 is unexplored. We examined the response of granule cell precursors to the overexpression of Hoxa2, which normally determines patterns of development specific to the hindbrain. How much does the development of the cerebellum, a midbrain/hindbrain structure, reflect its neuromeric origin as a hindbrain segment? RESULTS: We show that a Gbx2-positive, Otx2-/Hoxa2-negative territory corresponding to rhombomere 1 forms prior to an identifiable isthmic organiser. Early global overexpression of Hoxa2 at embryonic day 0 has no effect on the expression of isthmic signalling molecules or the allocation of rhombomere 1 territory, but selectively results in the loss of granule cell markers at embryonic day 6 and the depletion of cell bodies from the external granule cell layer. By comparison the trochlear nucleus and locus coeruleus form normally in ventral rhombomere 1 under these conditions. Microsurgery, coupled with electroporation, to target Hoxa2 overexpression to rhombic lip precursors, reveals a profound, autonomous respecification of migration. Rhombic lip derivatives, normally destined to occupy the external granule cell layer, violate the cerebellar boundary to form a ventrolateral nucleus in a position comparable to that occupied by rhombic lip derived neurons in rhombomere 2. CONCLUSIONS: Different overexpression strategies reveal that the recognition of migration cues by granule cell precursors is dependent on their identity as rhombomere 1 derivatives. Segmental patterning cues operate autonomously within the rhombic lip precursor pool. By contrast, a subset of coextensive nuclei is refractory to ectopic Hoxa2 and is presumably induced solely by isthmic organiser activity. Thus, graded (isthmic) and segmental mechanisms may operate exclusively of one another in the specification of different neuronal populations within rhombomere 1. The early designation of an Otx2-negative, Hoxa2-negative region, prior to the appearance of the isthmic organiser, is a key initial step in the specification of the cerebellum

CGIntrinsics: Better Intrinsic Image Decomposition through Physically-Based Rendering

Intrinsic image decomposition is a challenging, long-standing computer vision problem for which ground truth data is very difficult to acquire. We explore the use of synthetic data for training CNN-based intrinsic image decomposition models, then applying these learned models to real-world images. To that end, we present \ICG, a new, large-scale dataset of physically-based rendered images of scenes with full ground truth decompositions. The rendering process we use is carefully designed to yield high-quality, realistic images, which we find to be crucial for this problem domain. We also propose a new end-to-end training method that learns better decompositions by leveraging \ICG, and optionally IIW and SAW, two recent datasets of sparse annotations on real-world images. Surprisingly, we find that a decomposition network trained solely on our synthetic data outperforms the state-of-the-art on both IIW and SAW, and performance improves even further when IIW and SAW data is added during training. Our work demonstrates the suprising effectiveness of carefully-rendered synthetic data for the intrinsic images task.Comment: Paper for 'CGIntrinsics: Better Intrinsic Image Decomposition through Physically-Based Rendering' published in ECCV, 201

Learning Shape Priors for Single-View 3D Completion and Reconstruction

The problem of single-view 3D shape completion or reconstruction is challenging, because among the many possible shapes that explain an observation, most are implausible and do not correspond to natural objects. Recent research in the field has tackled this problem by exploiting the expressiveness of deep convolutional networks. In fact, there is another level of ambiguity that is often overlooked: among plausible shapes, there are still multiple shapes that fit the 2D image equally well; i.e., the ground truth shape is non-deterministic given a single-view input. Existing fully supervised approaches fail to address this issue, and often produce blurry mean shapes with smooth surfaces but no fine details. In this paper, we propose ShapeHD, pushing the limit of single-view shape completion and reconstruction by integrating deep generative models with adversarially learned shape priors. The learned priors serve as a regularizer, penalizing the model only if its output is unrealistic, not if it deviates from the ground truth. Our design thus overcomes both levels of ambiguity aforementioned. Experiments demonstrate that ShapeHD outperforms state of the art by a large margin in both shape completion and shape reconstruction on multiple real datasets.Comment: ECCV 2018. The first two authors contributed equally to this work. Project page: http://shapehd.csail.mit.edu

Childhood growth and development and DNA methylation age in mid-life

Background: In the first study of its kind, we examine the association between growth and development in early life and DNAm age biomarkers in mid-life. / Methods: Participants were from the Medical Research Council National Survey of Health and Development (n = 1376). Four DNAm age acceleration (AgeAccel) biomarkers were measured when participants were aged 53 years: AgeAccelHannum; AgeAccelHorvath; AgeAccelLevine; and AgeAccelGrim. Exposure variables included: relative weight gain (standardised residuals from models of current weight z-score on current height, and previous weight and height z-scores); and linear growth (standardised residuals from models of current height z-score on previous height and weight z-scores) during infancy (0–2 years, weight gain only), early childhood (2–4 years), middle childhood (4–7 years) and late childhood to adolescence (7–15 years); age at menarche; and pubertal stage for men at 14–15 years. The relationship between relative weight gain and linear growth and AgeAccel was investigated using conditional growth models. We replicated analyses from the late childhood to adolescence period and pubertal timing among 240 participants from The National Child and Development Study (NCDS). / Results: A 1SD increase in relative weight gain in late childhood to adolescence was associated with 0.50 years (95% CI 0.20, 0.79) higher AgeAccelGrim. Although the CI includes the null, the estimate was similar in NCDS [0.57 years (95% CI − 0.01, 1.16)] There was no strong evidence that relative weight gain and linear growth in childhood was associated with any other AgeAccel biomarker. There was no relationship between pubertal timing in men and AgeAccel biomarkers. Women who reached menarche ≥ 12 years had 1.20 years (95% CI 0.15, 2.24) higher AgeAccelGrim on average than women who reached menarche < 12 years; however, this was not replicated in NCDS and was not statistically significant after Bonferroni correction. / Conclusions: Our findings generally do not support an association between growth and AgeAccel biomarkers in mid-life. However, we found rapid weight gain during pubertal development, previously related to higher cardiovascular disease risk, to be associated with older AgeAccelGrim. Given this is an exploratory study, this finding requires replication

The human renal lymphatics under normal and pathological conditions

Ishikawa Y, Akasaka Y, Kiguchi H, Akishima-Fukasawa Y, Hasegawa T, Ito K, Kimura-Matsumoto M, Ishiguro S, Morita H, Sato S, Soh S & Ishii T (2006) Histopathology 49, 265–273 The human renal lymphatics under normal and pathological conditions AIMS: The renal lymphatics have not been fully documented in humans. The aim of this study was to clarify the morphology of the human renal lymphatic system under normal and pathological conditions by immunohistochemistry using anti-D2-40 antibody. METHODS AND RESULTS: Normal and pathological renal tissues obtained at autopsy as well as nephrectomy specimens with renal cell carcinoma (RCC) were used. Thin sections were immunostained with antibodies against D2-40 and CD31. In normal kidney, D2-40+ lymphatics were abundant in the interstitium around the interlobar and arcuate arteries/veins but sporadic in those around the glomeruli or between the tubules in the cortex. A few lymphatics contained erythrocytes in their lumina. Lymphatics were seldom present in the medulla. In RCC cases, lymphatics were evident at the tumour margin, whereas CD31+ capillaries were abundant throughout the tumour and lymphatics were increased in the fibrous interstitium around the tumour. Lymphatic invasion by RCC cells was also detectable. D2-40+ lymphatics were evident in other pathological conditions and end-stage kidney had a denser lymphatic distribution than normal kidney. CONCLUSIONS: Lymphatics are abundant around the arteries/veins and are also present in the renal cortex and medulla. D2-40 immunostaining is helpful for investigating the pathophysiological role of renal lymphatics

Signal-Locality and Subquantum Information in Deterministic Hidden-Variables Theories

It is proven that any deterministic hidden-variables theory, that reproduces quantum theory for a 'quantum equilibrium' distribution of hidden variables, must predict the existence of instantaneous signals at the statistical level for hypothetical 'nonequilibrium ensembles'. This 'signal-locality theorem' generalises yet another feature of the pilot-wave theory of de Broglie and Bohm, for which it is already known that signal-locality is true only in equilibrium. Assuming certain symmetries, lower bounds are derived on the 'degree of nonlocality' of the singlet state, defined as the (equilibrium) fraction of outcomes at one wing of an EPR-experiment that change in response to a shift in the distant angular setting. It is shown by explicit calculation that these bounds are satisfied by pilot-wave theory. The degree of nonlocality is interpreted as the average number of bits of 'subquantum information' transmitted superluminally, for an equilibrium ensemble. It is proposed that this quantity might provide a novel measure of the entanglement of a quantum state, and that the field of quantum information would benefit from a more explicit hidden-variables approach. It is argued that the signal-locality theorem supports the hypothesis, made elsewhere, that in the remote past the universe relaxed to a state of statistical equilibrium at the hidden-variable level, a state in which nonlocality happens to be masked by quantum noise