Prevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features.
We ...characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs.
Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5' end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours.
KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.
Cardiovascular disease (CVD) is a leading cause of death among women. CVD is associated with reduced quality of life, significant treatment and management costs, and lost productivity. Estimating the ...risk of CVD would help patients at a higher risk of CVD to initiate preventive measures to reduce risk of disease. The Framingham risk score and the QRISK® score are two risk prediction models used to evaluate future CVD risk in the UK. Although the algorithms perform well in the general population, they do not take into account pregnancy complications, which are well known risk factors for CVD in women and have been highlighted in a recent umbrella review. We plan to develop a robust CVD risk prediction model to assess the additional value of pregnancy risk factors in risk prediction of CVD in women postpartum.
Using candidate predictors from QRISK®-3, the umbrella review identified from literature and from discussions with clinical experts and patient research partners, we will use time-to-event Cox proportional hazards models to develop and validate a 10-year risk prediction model for CVD postpartum using Clinical Practice Research Datalink (CPRD) primary care database for development and internal validation of the algorithm and the Secure Anonymised Information Linkage (SAIL) databank for external validation. We will then assess the value of additional candidate predictors to the QRISK®-3 in our internal and external validations.
The developed risk prediction model will incorporate pregnancy-related factors which have been shown to be associated with future risk of CVD but have not been taken into account in current risk prediction models. Our study will therefore highlight the importance of incorporating pregnancy-related risk factors into risk prediction modeling for CVD postpartum.
Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β cells. The rapid rise in T1D incidence during the past 50 y suggests environmental factors contribute to the ...disease. The trillion symbiotic microorganisms inhabiting the mammalian gastrointestinal tract (i.e., the microbiota) influence numerous aspects of host physiology. In this study we review the evidence linking perturbations of the gut microbiome to pancreatic autoimmunity. We discuss data from rodent models demonstrating the essential role of the gut microbiota on the development and function of the host's mucosal and systemic immune systems. Furthermore, we review findings from human longitudinal cohort studies examining the influence of environmental and lifestyle factors on microbiota composition and pancreatic autoimmunity. Taken together, these data underscore the requirement for mechanistic studies to identify bacterial components and metabolites interacting with the innate and adaptive immune system, which would set the basis for preventative or therapeutic strategies in T1D.
Exogenous glucocorticoids inhibit neointimal proliferation in animals. We aimed to test the hypothesis that endogenous glucocorticoids influence neointimal proliferation; this may be mediated by ...effects on systemic risk factors or locally in vessels and modulated by either adrenal secretion or enzymes expressed in vessels that mediate local inactivation 11β-hydroxysteroid dehydrogenase type II (11β-HSD2) in endothelium or regeneration 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) in smooth muscle of glucocorticoids. Femoral artery wire angioplasty was conducted in C57BL/6J, Apo-E−/−, 11β-HSD1−/−, Apo-E, 11β-HSD1−/− (double knockout), and 11β-HSD2−/− mice after glucocorticoid administration, adrenalectomy, glucocorticoid or mineralocorticoid receptor antagonism, or selective 11β-HSD1 inhibition. In C57BL/6J mice, neointimal proliferation was reduced by systemic or local glucocorticoid administration, unaffected by adrenalectomy, reduced by the mineralocorticoid receptor antagonist eplerenone, and increased by the glucocorticoid receptor antagonist RU38486. 11β-HSD2 deletion had no effect on neointimal proliferation, with or without eplerenone. 11β-HSD1 inhibition or deletion had no effect in chow-fed C57BL/6J mice but reduced neointimal proliferation in Apo-E−/− mice on Western diet. Reductions in neointimal size were accompanied by reduced macrophage and increased collagen content. We conclude that pharmacological administration of glucocorticoid receptor agonists or of mineralocorticoid receptor antagonists may be useful in reducing neointimal proliferation. Endogenous corticosteroids induce beneficial glucocorticoid receptor activation and adverse mineralocorticoid receptor activation. However, manipulation of glucocorticoid metabolism has beneficial effects only in mice with exaggerated systemic risk factors, suggesting effects mediated primarily in liver and adipose rather than intravascular glucocorticoid signaling. Reducing glucocorticoid action with 11β-HSD1 inhibitors that are being developed for type 2 diabetes appears not to risk enhanced neointimal proliferation.
Bayesian statistical learning provides a coherent probabilistic framework for modelling uncertainty in systems. This review describes the theoretical foundations underlying Bayesian statistics and ...outlines the computational frameworks for implementing Bayesian inference in practice. We then describe the use of Bayesian learning in single-cell biology for the analysis of high-dimensional, large data sets.
BackgroundPreterm birth causes long-term problems, even for infants born 1 or 2 weeks early. However, less is known about infants born after their due date and over a quarter of infants are born over ...1 week late, and many still remain undelivered after 2 weeks. The aim of this work is to quantify the risks of infants developing encephalopathy when birth occurs after the due date, and if other proposed risk factors modify this relationship.MethodsThe dataset contain information on 4 036 346 infants born in Sweden between 1973 and 2012. Exposure was defined as birth 7, or more, days after the infants’ due date. The primary outcome was the development of neonatal encephalopathy (defined as seizures, encephalopathy or brain injury caused by asphyxia or with unspecified cause). Covariates were selected as presumed confounders a priori.Results28.4% infants were born 1 or more weeks after their due date. An infant’s risk of being born with encephalopathy was higher in the post 41 weeks group in the unadjusted (OR 1.40 (95% CI 1.32 to 1.49)) and final model (OR 1.38 (95% CI 1.29 to 1.47)), with the relative odds of encephalopathy increasing by an estimated 20% per week after the due date, and modified by maternal age (P=0.022).ConclusionsSingleton infants born at, or after, 41 weeks gestation have lower Apgar scores and higher risk of developing encephalopathy in the newborn period, and the association appeared more marked in older mothers. These data could be useful if provided to women as part of their decision-making.
Similar to tumor-initiating cells (TICs), minimal residual disease (MRD) is capable of reinitiating tumors and causing recurrence. However, the molecular characteristics of solid tumor MRD cells and ...drivers of their survival have remained elusive. Here we performed dense multiregion transcriptomics analysis of paired biopsies from 17 ovarian cancer patients before and after chemotherapy. We reveal that while MRD cells share important molecular signatures with TICs, they are also characterized by an adipocyte-like gene expression signature and a portion of them had undergone epithelial-mesenchymal transition (EMT). In a cell culture MRD model, MRD-mimic cells showed the same phenotype and were dependent on fatty acid oxidation (FAO) for survival and resistance to cytotoxic agents. These findings identify EMT and FAO as attractive targets to eradicate MRD in ovarian cancer and make a compelling case for the further testing of FAO inhibitors in treating MRD.
Correct positioning and morphology of the mitotic spindle is achieved through regulating the interaction between microtubules (MTs) and cortical actin. Here we find that, in the Drosophila ...melanogaster early embryo, reduced levels of the protein kinase Akt result in incomplete centrosome migration around cortical nuclei, bent mitotic spindles, and loss of nuclei into the interior of the embryo. We show that Akt is enriched at the embryonic cortex and is required for phosphorylation of the glycogen synthase kinase-3β homologue Zeste-white 3 kinase (Zw3) and for the cortical localizations of the adenomatosis polyposis coli (APC)-related protein APC2/E-APC and the MT + Tip protein EB1. We also show that reduced levels of Akt result in mislocalization of APC2 in postcellularized embryonic mitoses and misorientation of epithelial mitotic spindles. Together, our results suggest that Akt regulates a complex containing Zw3, Armadillo, APC2, and EB1 and that this complex has a role in stabilizing MT-cortex interactions, facilitating both centrosome separation and mitotic spindle orientation.
Abstract
Motivation
Pseudotime estimation from single-cell gene expression data allows the recovery of temporal information from otherwise static profiles of individual cells. Conventional pseudotime ...inference methods emphasize an unsupervised transcriptome-wide approach and use retrospective analysis to evaluate the behaviour of individual genes. However, the resulting trajectories can only be understood in terms of abstract geometric structures and not in terms of interpretable models of gene behaviour.
Results
Here we introduce an orthogonal Bayesian approach termed ‘Ouija’ that learns pseudotimes from a small set of marker genes that might ordinarily be used to retrospectively confirm the accuracy of unsupervised pseudotime algorithms. Crucially, we model these genes in terms of switch-like or transient behaviour along the trajectory, allowing us to understand why the pseudotimes have been inferred and learn informative parameters about the behaviour of each gene. Since each gene is associated with a switch or peak time the genes are effectively ordered along with the cells, allowing each part of the trajectory to be understood in terms of the behaviour of certain genes. We demonstrate that this small panel of marker genes can recover pseudotimes that are consistent with those obtained using the entire transcriptome. Furthermore, we show that our method can detect differences in the regulation timings between two genes and identify ‘metastable’ states—discrete cell types along the continuous trajectories—that recapitulate known cell types.
Availability and implementation
An open source implementation is available as an R package at http://www.github.com/kieranrcampbell/ouija and as a Python/TensorFlow package at http://www.github.com/kieranrcampbell/ouijaflow.
Supplementary information
Supplementary data are available at Bioinformatics online.
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