The effect of a supplementary ('Gist-based') information leaflet on colorectal cancer knowledge and screening intention: a randomized controlled trial.

Guided by Fuzzy Trace Theory, this study examined the impact of a 'Gist-based' leaflet on colorectal cancer screening knowledge and intentions; and tested the interaction with participants' numerical ability. Adults aged 45-59 years from four UK general practices were randomly assigned to receive standard information ('The Facts', n = 2,216) versus standard information plus 'The Gist' leaflet (Gist + Facts, n = 2,236). Questionnaires were returned by 964/4,452 individuals (22 %). 82 % of respondents reported having read the information, but those with poor numeracy were less likely (74 vs. 88 %, p < .001). The 'Gist + Facts' group were more likely to reach the criterion for adequate knowledge (95 vs. 91 %; p < .01), but this was not moderated by numeracy. Most respondents (98 %) intended to participate in screening, with no group differences and no interaction with numeracy. The improved levels of knowledge and self-reported reading suggest 'The Gist' leaflet may increase engagement with colorectal cancer screening, but ceiling effects reduced the likelihood that screening intentions would be affected

Regulation of microRNA biogenesis and turnover by animals and their viruses

Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Risk perception among Brazilian individuals with high risk for colorectal cancer and colonoscopy

<p>Abstract</p> <p>Background</p> <p>Risk perception is considered a motivating factor for adopting preventive behaviors. This study aimed to verify the demographic characteristics and cancer family history that are predictors of risk perception and to verify if risk perception is a predictor of colonoscopy adherence.</p> <p>Methods</p> <p>Individuals with a family colorectal cancer history as indicated by a proband with cancer were interviewed by telephone. They responded to a questionnaire covering demographic characteristics, colonoscopy history and four questions on risk perception. Tests of multiple linear regression and logistic regression were used to identify associations between dependent and independent variables.</p> <p>Results</p> <p>The 117 participants belonged to 62 families and had a mean age of 45.2 years. The majority of these individuals were female (74.4%) and from families who met the Amsterdam Criteria (54.7%). The average risk perception was 47.6%, with a median of 50%. The average population perception of individual risk was 55.4%, with a median of 50%. Variables associated with a higher risk perception were age, gender, religion, school level, income, and death of a family member. The variable predicting colonoscopy was receiving medical information regarding risk (odds ratio OR 8.40).</p> <p>Conclusions</p> <p>We found that family cancer history characteristics (number of relatives with cancer, risk classification) are associated with adequate risk perception. Risk perception does not predict colonoscopy in this sample. The only variable that predicted colonoscopy was receiving medical information recommending screening.</p

Microstructural evolution and trace element mobility in Witwatersrand pyrite

Microstructural analysis of pyrite from a single sample of Witwatersrand conglomerate indicates a complex deformation history involving components of both plastic and brittle deformation. Internal deformation associated with dislocation creep is heterogeneously developed within grains, shows no systematic relationship to bulk rock strain or the location of grain boundaries and is interpreted to represent an episode of pyrite deformation that predates the incorporation of detrital pyrite grains into the Central Rand conglomerates. In contrast, brittle deformation, manifest by grain fragmentation that transects dislocation-related microstructures, is spatially related to grain contacts and is interpreted to represent post-depositional deformation of the Central Rand conglomerates. Analysis of the low-angle boundaries associated with the early dislocation creep phase of deformation indicates the operation of {100} slip systems. However, some orientation boundaries have geometrical characteristics that are not consistent with simple {100} deformation.These boundaries may represent the combination of multiple slip systems or the operation of the previously unrecognized {120} slip system. These boundaries are associated with order of magnitude enrichments in As, Ni and Co that indicate a deformation control on the remobilization of trace elements within pyrite and a potential slip system control on the effectiveness of fast-diffusion pathways. The results confirm the importance of grain-scale elemental remobilization within pyrite prior to their incorporation into the Witwatersrand gold-bearing conglomerates. Since the relationship between gold and pyrite is intimately related to the trace element geochemistry of pyrite, the results have implications for the application of minor element geochemistry to ore deposit formation, suggest a reason for heterogeneous conductivity and localized gold precipitation in natural pyrite and provide a framework for improving mineral processing

Intron Evolution: Testing Hypotheses of Intron Evolution Using the Phylogenomics of Tetraspanins

BACKGROUND: Although large scale informatics studies on introns can be useful in making broad inferences concerning patterns of intron gain and loss, more specific questions about intron evolution at a finer scale can be addressed using a gene family where structure and function are well known. Genome wide surveys of tetraspanins from a broad array of organisms with fully sequenced genomes are an excellent means to understand specifics of intron evolution. Our approach incorporated several new fully sequenced genomes that cover the major lineages of the animal kingdom as well as plants, protists and fungi. The analysis of exon/intron gene structure in such an evolutionary broad set of genomes allowed us to identify ancestral intron structure in tetraspanins throughout the eukaryotic tree of life. METHODOLOGY/PRINCIPAL FINDINGS: We performed a phylogenomic analysis of the intron/exon structure of the tetraspanin protein family. In addition, to the already characterized tetraspanin introns numbered 1 through 6 found in animals, three additional ancient, phase 0 introns we call 4a, 4b and 4c were found. These three novel introns in combination with the ancestral introns 1 to 6, define three basic tetraspanin gene structures which have been conserved throughout the animal kingdom. Our phylogenomic approach also allows the estimation of the time at which the introns of the 33 human tetraspanin paralogs appeared, which in many cases coincides with the concomitant acquisition of new introns. On the other hand, we observed that new introns (introns other than 1-6, 4a, b and c) were not randomly inserted into the tetraspanin gene structure. The region of tetraspanin genes corresponding to the small extracellular loop (SEL) accounts for only 10.5% of the total sequence length but had 46% of the new animal intron insertions. CONCLUSIONS/SIGNIFICANCE: Our results indicate that tests of intron evolution are strengthened by the phylogenomic approach with specific gene families like tetraspanins. These tests add to our understanding of genomic innovation coupled to major evolutionary divergence events, functional constraints and the timing of the appearance of evolutionary novelty

The Making of a Monster: Postnatal Ontogenetic Changes in Craniomandibular Shape in the Great Sabercat Smilodon

Derived sabercats had craniomandibular morphologies that in many respects were highly different from those of extant felids, and this has often been interpreted functionally as adaptations for predation at extreme gape angles with hypertrophied upper canines. It is unknown how much of this was a result of intraspecific postnatal ontogeny, since juveniles of sabercats are rare and no quantitative study has been made of craniomandibular ontogeny. Postnatal ontogenetic craniomandibular shape changes in two morphologically derived sabercats, Smilodon fatalis and S. populator, were analysed using geometric morphometrics and compared to three species of extant pantherines, the jaguar, tiger, and Sunda clouded leopard. Ontogenetic shape changes in Smilodon usually involved the same areas of the cranium and mandible as in extant pantherines, and large-scale modularization was similar, suggesting that such may have been the case for all felids, since it followed the same trends previously observed in other mammals. However, in other respects Smilodon differed from extant pantherines. Their crania underwent much greater and more localised ontogenetic shape changes than did the mandibles, whereas crania and mandibles of extant pantherines underwent smaller, fewer and less localised shape changes. Ontogenetic shape changes in the two species of Smilodon are largely similar, but differences are also present, notably those which may be tied to the presence of larger upper canines in S. populator. Several of the specialized cranial characters differentiating adult Smilodon from extant felids in a functional context, which are usually regarded as evolutionary adaptations for achieving high gape angles, are ontogenetic, and in several instances ontogeny appears to recapitulate phylogeny to some extent. No such ontogenetic evolutionary adaptive changes were found in the extant pantherines. Evolution in morphologically derived sabercats involved greater cranial ontogenetic changes than among extant felids, resulting in greatly modified adult craniomandibular morphologies

Deep Sequencing of Human Nuclear and Cytoplasmic Small RNAs Reveals an Unexpectedly Complex Subcellular Distribution of miRNAs and tRNA 3′ Trailers

MicroRNAs (miRNAs) are ∼22-nt small non-coding regulatory RNAs that have generally been considered to regulate gene expression at the post-transcriptional level in the cytoplasm. However, recent studies have reported that some miRNAs localize to and function in the nucleus.To determine the number of miRNAs localized to the nucleus, we systematically investigated the subcellular distribution of small RNAs (sRNAs) by independent deep sequencing sequenced of the nuclear and cytoplasmic pools of 18- to 30-nucleotide sRNAs from human cells. We identified 339 nuclear and 324 cytoplasmic known miRNAs, 300 of which overlap, suggesting that the majority of miRNAs are imported into the nucleus. With the exception of a few miRNAs evidently enriched in the nuclear pool, such as the mir-29b, the ratio of miRNA abundances in the nuclear fraction versus in the cytoplasmic fraction vary to some extent. Moreover, our results revealed that a large number of tRNA 3′trailers are exported from the nucleus and accumulate in the cytoplasm. These tRNA 3′ trailers accumulate in a variety of cell types, implying that the biogenesis of tRNA 3′ trailers is conserved and that they have a potential functional role in vertebrate cells.Our results provide the first comprehensive view of the subcellular distribution of diverse sRNAs and new insights into the roles of miRNAs and tRNA 3′ trailers in the cell

High-Throughput High-Resolution Class I HLA Genotyping in East Africa

HLA, the most genetically diverse loci in the human genome, play a crucial role in host-pathogen interaction by mediating innate and adaptive cellular immune responses. A vast number of infectious diseases affect East Africa, including HIV/AIDS, malaria, and tuberculosis, but the HLA genetic diversity in this region remains incompletely described. This is a major obstacle for the design and evaluation of preventive vaccines. Available HLA typing techniques, that provide the 4-digit level resolution needed to interpret immune responses, lack sufficient throughput for large immunoepidemiological studies. Here we present a novel HLA typing assay bridging the gap between high resolution and high throughput. The assay is based on real-time PCR using sequence-specific primers (SSP) and can genotype carriers of the 49 most common East African class I HLA-A, -B, and -C alleles, at the 4-digit level. Using a validation panel of 175 samples from Kampala, Uganda, previously defined by sequence-based typing, the new assay performed with 100% sensitivity and specificity. The assay was also implemented to define the HLA genetic complexity of a previously uncharacterized Tanzanian population, demonstrating its inclusion in the major East African genetic cluster. The availability of genotyping tools with this capacity will be extremely useful in the identification of correlates of immune protection and the evaluation of candidate vaccine efficacy

Sp6 and Sp8 transcription factors control AER formation and dorsal-ventral patterning in limb development

The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6;Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6-/-;Sp8+/-) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/βcatenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning