Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses ...of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.
Pain visual analogue scales (VAS) are commonly used in clinical trials and are often treated as an interval level scale without evidence that this is appropriate. This paper examines the internal ...construct validity and responsiveness of the pain VAS using Rasch analysis.
Patients (n = 221, mean age 67, 58% female) with chronic stable joint pain (hip 40% or knee 60%) of mechanical origin waiting for joint replacement were included. Pain was scored on seven daily VASs. Rasch analysis was used to examine fit to the Rasch model. Responsiveness (Standardized Response Means, SRM) was examined on the raw ordinal data and the interval data generated from the Rasch analysis.
Baseline pain VAS scores fitted the Rasch model, although 15 aberrant cases impacted on unidimensionality. There was some local dependency between items but this did not significantly affect the person estimates of pain. Daily pain (item difficulty) was stable, suggesting that single measures can be used. Overall, the SRMs derived from ordinal data overestimated the true responsiveness by 59%. Changes over time at the lower and higher end of the scale were represented by large jumps in interval equivalent data points; in the middle of the scale the reverse was seen.
The pain VAS is a valid tool for measuring pain at one point in time. However, the pain VAS does not behave linearly and SRMs vary along the trait of pain. Consequently, Minimum Clinically Important Differences using raw data, or change scores in general, are invalid as these will either under- or overestimate true change; raw pain VAS data should not be used as a primary outcome measure or to inform parametric-based Randomised Controlled Trial power calculations in research studies; and Rasch analysis should be used to convert ordinal data to interval data prior to data interpretation.
Despite the large evolutionary distances between metazoan species, they can show remarkable commonalities in their biology, and this has helped to establish fly and worm as model organisms for human ...biology. Although studies of individual elements and factors have explored similarities in gene regulation, a large-scale comparative analysis of basic principles of transcriptional regulatory features is lacking. Here we map the genome-wide binding locations of 165 human, 93 worm and 52 fly transcription regulatory factors, generating a total of 1,019 data sets from diverse cell types, developmental stages, or conditions in the three species, of which 498 (48.9%) are presented here for the first time. We find that structural properties of regulatory networks are remarkably conserved and that orthologous regulatory factor families recognize similar binding motifs in vivo and show some similar co-associations. Our results suggest that gene-regulatory properties previously observed for individual factors are general principles of metazoan regulation that are remarkably well-preserved despite extensive functional divergence of individual network connections. The comparative maps of regulatory circuitry provided here will drive an improved understanding of the regulatory underpinnings of model organism biology and how these relate to human biology, development and disease.
Organisms must respond to hypoxia to preserve oxygen homeostasis. We identify a thiol oxidase, previously assigned as cysteamine (2-aminoethanethiol) dioxygenase (ADO), as a low oxygen affinity ...(high-
O
) amino-terminal cysteine dioxygenase that transduces the oxygen-regulated stability of proteins by the N-degron pathway in human cells. ADO catalyzes the conversion of amino-terminal cysteine to cysteine sulfinic acid and is related to the plant cysteine oxidases that mediate responses to hypoxia by an identical posttranslational modification. We show in human cells that ADO regulates RGS4/5 (regulator of G protein signaling) N-degron substrates, modulates G protein-coupled calcium ion signals and mitogen-activated protein kinase activity, and that its activity extends to other N-cysteine proteins including the angiogenic cytokine interleukin-32. Identification of a conserved enzymatic oxygen sensor in multicellular eukaryotes opens routes to better understanding and therapeutic targeting of adaptive responses to hypoxia.
Gonorrhoea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men ...(MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single-dose treatment for gonorrhoea from 2005 to 2010, during which time resistance increased, and subsequently declined.
We developed a stochastic compartmental model representing the natural history and transmission of cefixime-sensitive and cefixime-resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with 37% (95% credible interval CrI 24%-52%) of infections remaining asymptomatic and untreated, accounting for 89% (95% CrI 82%-93%) of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 83% (95% CrI 53%-99%) of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% (95% CrI 26%-36%) of cases were treated with cefixime, and when more than 55% (95% CrI 44%-66%) of cases were treated with cefixime, the resistant strain had a net fitness advantage over the susceptible strain. Limitations include sparse data leading to large intervals on key model parameters and necessary assumptions in the modelling of a complex epidemiological process.
Our study provides, to our knowledge, the first estimates of the fitness cost and benefit associated with resistance of the gonococcus to a clinically relevant antibiotic. Our findings have important implications for antibiotic stewardship and public health policies and, in particular, suggest that a previously abandoned antibiotic could be used again to treat a minority of gonorrhoea cases without raising resistance levels.
Marine protected areas (MPAs) are increasingly being used globally to conserve marine resources. However, whether many MPAs are being effectively and equitably managed, and how MPA management ...influences substantive outcomes remain unknown. We developed a global database of management and fish population data (433 and 218 MPAs, respectively) to assess: MPA management processes; the effects of MPAs on fish populations; and relationships between management processes and ecological effects. Here we report that many MPAs failed to meet thresholds for effective and equitable management processes, with widespread shortfalls in staff and financial resources. Although 71% of MPAs positively influenced fish populations, these conservation impacts were highly variable. Staff and budget capacity were the strongest predictors of conservation impact: MPAs with adequate staff capacity had ecological effects 2.9 times greater than MPAs with inadequate capacity. Thus, continued global expansion of MPAs without adequate investment in human and financial capacity is likely to lead to sub-optimal conservation outcomes.
Children who receive a diagnosis of fetal alcohol spectrum disorder may have a characteristic facial appearance in addition to neurodevelopmental impairment. It is not well understood whether there ...is a gradient of facial characteristics of children who did not receive a diagnosis of fetal alcohol spectrum disorder but who were exposed to a range of common drinking patterns during pregnancy.
To examine the association between dose, frequency, and timing of prenatal alcohol exposure and craniofacial phenotype in 12-month-old children.
A prospective cohort study was performed from January 1, 2011, to December 30, 2014, among mothers recruited in the first trimester of pregnancy from low-risk, public maternity clinics in metropolitan Melbourne, Australia. A total of 415 white children were included in this analysis of 3-dimensional craniofacial images taken at 12 months of age. Analysis was performed with objective, holistic craniofacial phenotyping using dense surface models of the face and head. Partial least square regression models included covariates known to affect craniofacial shape.
Low, moderate to high, or binge-level alcohol exposure in the first trimester or throughout pregnancy.
Anatomical differences in global and regional craniofacial shape between children of women who abstained from alcohol during pregnancy and children with varying levels of prenatal alcohol exposure.
Of the 415 children in the study (195 girls and 220 boys; mean SD age, 363.0 8.3 days), a consistent association between craniofacial shape and prenatal alcohol exposure was observed at almost any level regardless of whether exposure occurred only in the first trimester or throughout pregnancy. Regions of difference were concentrated around the midface, nose, lips, and eyes. Directional visualization showed that these differences corresponded to general recession of the midface and superior displacement of the nose, especially the tip of the nose, indicating shortening of the nose and upturning of the nose tip. Differences were most pronounced between groups with no exposure and groups with low exposure in the first trimester (forehead), moderate to high exposure in the first trimester (eyes, midface, chin, and parietal region), and binge-level exposure in the first trimester (chin).
Prenatal alcohol exposure, even at low levels, can influence craniofacial development. Although the clinical significance of these findings is yet to be determined, they support the conclusion that for women who are or may become pregnant, avoiding alcohol is the safest option.
Despite progress in TB control in low-burden countries like England and Wales, there are still diagnostic delays. Molecular testing and/or whole-genome sequencing (WGS) provide more rapid diagnosis ...but their cost-effectiveness is relatively unexplored in low-burden settings.
An integrated transmission-dynamic health economic model is used to assess the cost-effectiveness of using WGS to replace culture-based drug-sensitivity testing, versus using molecular testing versus combined use of WGS and molecular testing, for routine TB diagnosis. The model accounts for the effects of faster appropriate treatment in reducing transmission, benefiting health and reducing future treatment costs. Cost-effectiveness is assessed using incremental net benefit (INB) over a 10-year horizon with a quality-adjusted life-year valued at £20 000, and discounting at 3.5% per year.
WGS shortens the time to drug sensitivity testing and treatment modification where necessary, reducing treatment and hospitalisation costs, with an INB of £7.1 million. Molecular testing shortens the time to TB diagnosis and treatment. Initially, this causes an increase in annual costs of treatment, but averting transmissions and future active TB disease subsequently, resulting in cost savings and health benefits to achieve an INB of £8.6 million (GeneXpert MTB/RIF) or £11.1 million (Xpert-Ultra). Combined use of Xpert-Ultra and WGS is the optimal strategy we consider, with an INB of £16.5 million.
Routine use of WGS or molecular testing is cost-effective in a low-burden setting, and combined use is the most cost-effective option. Adoption of these technologies can help low-burden countries meet the WHO End TB Strategy milestones, particularly the UK, which still has relatively high TB rates.
Chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) has become a valuable and widely used approach for mapping the genomic location of transcription-factor ...binding and histone modifications in living cells. Despite its widespread use, there are considerable differences in how these experiments are conducted, how the results are scored and evaluated for quality, and how the data and metadata are archived for public use. These practices affect the quality and utility of any global ChIP experiment. Through our experience in performing ChIP-seq experiments, the ENCODE and modENCODE consortia have developed a set of working standards and guidelines for ChIP experiments that are updated routinely. The current guidelines address antibody validation, experimental replication, sequencing depth, data and metadata reporting, and data quality assessment. We discuss how ChIP quality, assessed in these ways, affects different uses of ChIP-seq data. All data sets used in the analysis have been deposited for public viewing and downloading at the ENCODE (http://encodeproject.org/ENCODE/) and modENCODE (http://www.modencode.org/) portals.
ABSTRACT
Well‐designed and effectively managed networks of marine reserves can be effective tools for both fisheries management and biodiversity conservation. Connectivity, the demographic linking of ...local populations through the dispersal of individuals as larvae, juveniles or adults, is a key ecological factor to consider in marine reserve design, since it has important implications for the persistence of metapopulations and their recovery from disturbance. For marine reserves to protect biodiversity and enhance populations of species in fished areas, they must be able to sustain focal species (particularly fishery species) within their boundaries, and be spaced such that they can function as mutually replenishing networks whilst providing recruitment subsidies to fished areas. Thus the configuration (size, spacing and location) of individual reserves within a network should be informed by larval dispersal and movement patterns of the species for which protection is required. In the past, empirical data regarding larval dispersal and movement patterns of adults and juveniles of many tropical marine species have been unavailable or inaccessible to practitioners responsible for marine reserve design. Recent empirical studies using new technologies have also provided fresh insights into movement patterns of many species and redefined our understanding of connectivity among populations through larval dispersal. Our review of movement patterns of 34 families (210 species) of coral reef fishes demonstrates that movement patterns (home ranges, ontogenetic shifts and spawning migrations) vary among and within species, and are influenced by a range of factors (e.g. size, sex, behaviour, density, habitat characteristics, season, tide and time of day). Some species move <0.1–0.5 km (e.g. damselfishes, butterflyfishes and angelfishes), <0.5–3 km (e.g. most parrotfishes, goatfishes and surgeonfishes) or 3–10 km (e.g. large parrotfishes and wrasses), while others move tens to hundreds (e.g. some groupers, emperors, snappers and jacks) or thousands of kilometres (e.g. some sharks and tuna). Larval dispersal distances tend to be <5–15 km, and self‐recruitment is common. Synthesising this information allows us, for the first time, to provide species, specific advice on the size, spacing and location of marine reserves in tropical marine ecosystems to maximise benefits for conservation and fisheries management for a range of taxa. We recommend that: (i) marine reserves should be more than twice the size of the home range of focal species (in all directions), thus marine reserves of various sizes will be required depending on which species require protection, how far they move, and if other effective protection is in place outside reserves; (ii) reserve spacing should be <15 km, with smaller reserves spaced more closely; and (iii) marine reserves should include habitats that are critical to the life history of focal species (e.g. home ranges, nursery grounds, migration corridors and spawning aggregations), and be located to accommodate movement patterns among these. We also provide practical advice for practitioners on how to use this information to design, evaluate and monitor the effectiveness of marine reserve networks within broader ecological, socioeconomic and management contexts.
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