Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Outcomes in randomised controlled trials in prevention and management of carious lesions:a systematic review

Abstract Background Inconsistent outcome reporting is one significant hurdle to combining results from trials into systematic reviews. Core outcome sets (COS) can reduce this barrier. The aim of this review was to map outcomes reported in caries prevention and management randomised controlled trials (RCT) as a first step to COS development. We also investigated RCT characteristics and reporting of primary outcomes and sample size calculations. Methods PubMed, Embase, Web of Knowledge and Cochrane CENTRAL were systematically searched (1 January 1968 to 25 August 2015). Inclusion criteria: RCTs comparing any technique for prevention or management of caries with another or placebo and RCTs comparing interventions to support patients undergoing treatment of caries (without setting, dentition or age restrictions). Categories were developed through piloting and group consensus and outcomes grouped accordingly. Results Of 4773 search results, 764 were potentially relevant, full text was available for 731 papers and 605 publications met the inclusion criteria and were included. For all outcomes across the time periods 1968–1980 and 2001–2010, reporting of outcome ‘caries experience’ reduced from 39% to 18%; ‘clinical performance of the restoration’ reporting increased from 33% to 42% although there was a reduction to 22% in 2011–2015. Emerging outcome domains include ‘lesion activity’ and ‘pulp health-related outcomes’, accounting for 1% and 0%, respectively, during 1968–1980 and 10% and 4% for 2011–2015. Reporting ‘resource efficiency’ and ‘quality of life measures’ have remained at a low level. No publications reported tooth survival independent of an index such as DMFT or equivalent. Primary outcomes were only identified as such in 414 (68%) of the reports. Conclusions Over the past 50 years, outcome reporting for trials on prevention and management of carious lesions have tended to focus on outcomes measuring caries experience and restoration material clinical performance with lesion activity and cost-effectiveness increasingly being reported. Patient-reported and patient-focused outcomes are becoming more common (although as secondary outcomes) but remain low in use. The challenge with developing a COS will be balancing commonly previously reported outcomes against those more relevant for the future. Trial registration PROSPERO, CRD42015025310 . Registered on 14 August 2015, Trials (Schwendicke et al., Trials 16:397, 2015) and COMET initiative online (COMET, 2017)

The over-representation of binary DNA tracts in seven sequenced chromosomes

BACKGROUND: DNA tracts composed of only two bases are possible in six combinations: A+G (purines, R), C+T (pyrimidines, Y), G+T (Keto, K), A+C (Imino, M), A+T (Weak, W) and G+C (Strong, S). It is long known that all-pyrimidine tracts, complemented by all-purines tracts ("R.Y tracts"), are excessively present in analyzed DNA. We have previously shown that R.Y tracts are in vast excess in yeast promoters, and brought evidence for their role in gene regulation. Here we report the systematic mapping of all six binary combinations on the level of complete sequenced chromosomes, as well as in their different subregions. RESULTS: DNA tracts composed of the above binary base combinations have been mapped in seven sequenced chromosomes: Human chromosomes 21 and 22 (the major contigs); Drosophila melanogaster chr. 2R; Caenorhabditis elegans chr. I; Arabidopsis thaliana chr. II; Saccharomyces cerevisiae chr. IV and M. jannaschii. A huge over-representation, reaching million-folds, has been found for very long tracts of all binary motifs except S, in each of the seven organisms. Long R.Y tracts are the most excessive, except in D. melanogaster, where the K.M motif predominates. S (G, C rich) tracts are in excess mainly in CpG islands; the W motif predominates in bacteria. Many excessively long W tracts are nevertheless found also in the archeon and in the eukaryotes. The survey of complete chromosomes enables us, for the first time, to map systematically the intergenic regions. In human and other chromosomes we find the highest over-representation of the binary DNA tracts in the intergenic regions. These over-representations are only partly explainable by the presence of interspersed elements. CONCLUSIONS: The over-representation of long DNA tracts composed of five of the above motifs is the largest deviation from randomness so far established for DNA, and this in a wide range of eukaryotic and archeal chromosomes. A propensity for ready DNA unwinding is proposed as the functional role, explaining the evolutionary conservation of the huge excesses observed

Mapping the prion protein distribution in marsupials: insights from comparing opossum with mouse CNS

The cellular form of the prion protein (PrP(C)) is a sialoglycoprotein widely expressed in the central nervous system (CNS) of mammalian species during neurodevelopment and in adulthood. The location of the protein in the CNS may play a role in the susceptibility of a species to fatal prion diseases, which are also known as the transmissible spongiform encephalopathies (TSEs). To date, little is known about PrP(C) distribution in marsupial mammals, for which no naturally occurring prion diseases have been reported. To extend our understanding of varying PrP(C) expression profiles in different mammals we carried out a detailed expression analysis of PrP(C) distribution along the neurodevelopment of the metatherian South American short-tailed opossum (Monodelphis domestica). We detected lower levels of PrP(C) in white matter fiber bundles of opossum CNS compared to mouse CNS. This result is consistent with a possible role for PrP(C) in the distinct neurodevelopment and neurocircuitry found in marsupials compared to other mammalian species

A systematic review of interactive multimedia interventions to promote children's communication with health professionals: implications for communicating with overweight children

Background: Interactive multimedia is an emerging technology that is being used to facilitate interactions between patients and health professionals. The purpose of this review was to identify and evaluate the impact of multimedia interventions (MIs), delivered in the context of paediatric healthcare, in order to inform the development of a MI to promote the communication of dietetic messages with overweight preadolescent children. Of particular interest were the effects of these MIs on child engagement and participation in treatment, and the subsequent effect on health-related treatment outcomes. Methods: An extensive search of 12 bibliographic databases was conducted in April 2012. Studies were included if: one or more child-participant was 7 to 11 years-of-age; a MI was used to improve health-related behaviour; child-participants were diagnosed with a health condition and were receiving treatment for that condition at the time of the study. Data describing study characteristics and intervention effects on communication, satisfaction, knowledge acquisition, changes in self-efficacy, healthcare utilisation, and health outcomes were extracted and summarised using qualitative and quantitative methods. Results: A total of 14 controlled trials, published between 1997 and 2006 met the selection criteria. Several MIs had the capacity to facilitate engagement between the child and a clinician, but only one sought to utilise the MI to improve communication between the child and health professional. In spite of concerns over the quality of some studies and small study populations, MIs were found useful in educating children about their health, and they demonstrated potential to improve children’s health- related self-efficacy, which could make them more able partners in face-to-face communications with health professionals. Conclusions: The findings of this review suggest that MIs have the capacity to support preadolescent child-clinician communication, but further research in this field is needed. Particular attention should be given to designing appropriate MIs that are clinically relevant

A Mammalian Conserved Element Derived from SINE Displays Enhancer Properties Recapitulating Satb2 Expression in Early-Born Callosal Projection Neurons

Short interspersed repetitive elements (SINEs) are highly repeated sequences that account for a significant proportion of many eukaryotic genomes and are usually considered “junk DNA”. However, we previously discovered that many AmnSINE1 loci are evolutionarily conserved across mammalian genomes, suggesting that they may have acquired significant functions involved in controlling mammalian-specific traits. Notably, we identified the AS021 SINE locus, located 390 kbp upstream of Satb2. Using transgenic mice, we showed that this SINE displays specific enhancer activity in the developing cerebral cortex. The transcription factor Satb2 is expressed by cortical neurons extending axons through the corpus callosum and is a determinant of callosal versus subcortical projection. Mouse mutants reveal a crucial function for Sabt2 in corpus callosum formation. In this study, we compared the enhancer activity of the AS021 locus with Satb2 expression during telencephalic development in the mouse. First, we showed that the AS021 enhancer is specifically activated in early-born Satb2+ neurons. Second, we demonstrated that the activity of the AS021 enhancer recapitulates the expression of Satb2 at later embryonic and postnatal stages in deep-layer but not superficial-layer neurons, suggesting the possibility that the expression of Satb2 in these two subpopulations of cortical neurons is under genetically distinct transcriptional control. Third, we showed that the AS021 enhancer is activated in neurons projecting through the corpus callosum, as described for Satb2+ neurons. Notably, AS021 drives specific expression in axons crossing through the ventral (TAG1−/NPY+) portion of the corpus callosum, confirming that it is active in a subpopulation of callosal neurons. These data suggest that exaptation of the AS021 SINE locus might be involved in enhancement of Satb2 expression, leading to the establishment of interhemispheric communication via the corpus callosum, a eutherian-specific brain structure

Towards the Development of an Empirical Model for Islamic Corporate Social Responsibility: Evidence from the Middle East

Academic research suggests that variances in contextual dynamics, and more specifically religion, may lead to disparate perceptions and practices of corporate social responsibility (CSR). Driven by the increased geopolitical and economic importance of the Middle East and identified gaps in knowledge, the study aims to examine if indeed there is a divergent form of CSR exercised in the region. The study identifies unique CSR dimensions and constructs presented through an empirical framework in order to outline the practice and perception of CSR in a context with strong Islamic beliefs. The framework goes beyond the platform of mere Islamic philanthropy and is based on CSR-stakeholder management practices. Following an exploratory research design and collecting interview data from representatives of 63 organisations from Saudi Arabia, the United Arab Emirates and Oman, the study offers a snapshot of the CSR reality from the perspective of those living the phenomenon. The results suggest that the practice and perception of CSR in the examined context are largely grounded in the areas of social and altruistic actions but they cannot be examined in isolation from the religious context of CSR operation. This focus is mainly attributed to the dominant role of Islam in the examined sample, which leads to forms of non-structured or semi-structured approaches to CSR. Apart from the theoretical advancements offered to the CSR literature, the study also provides contributions for practitioners and policy makers.</p

Pan-cancer deconvolution of tumour composition using DNA methylation

The nature and extent of immune cell infiltration into solid tumours are key determinants of therapeutic response. Here, using a DNA methylation-based approach to tumour cell fraction deconvolution, we report the integrated analysis of tumour composition and genomics across a wide spectrum of solid cancers. Initially studying head and neck squamous cell carcinoma, we identify two distinct tumour subgroups: ‘immune hot’ and ‘immune cold’, which display differing prognosis, mutation burden, cytokine signalling, cytolytic activity and oncogenic driver events. We demonstrate the existence of such tumour subgroups pan-cancer, link clonal-neoantigen burden to cytotoxic T-lymphocyte infiltration, and show that transcriptional signatures of hot tumours are selectively engaged in immunotherapy responders. We also find that treatment-naive hot tumours are markedly enriched for known immune-resistance genomic alterations, potentially explaining the heterogeneity of immunotherapy response and prognosis seen within this group. Finally, we define a catalogue of mediators of active antitumour immunity, deriving candidate biomarkers and potential targets for precision immunotherapy

Classifying the evolutionary and ecological features of neoplasms

The consensus conference was supported by Wellcome Genome Campus Advanced Courses and Scientific Conferences. C.C.M. is supported in part by US NIH grants P01 CA91955, R01 CA149566, R01 CA170595, R01 CA185138 and R01 CA140657 as well as CDMRP Breast Cancer Research Program Award BC132057. M.J. is supported by NIH grant K99CA201606. K.S.A. is supported by NCI 5R21 CA196460. K. Polyak is supported by R35 CA197623, U01 CA195469, U54 CA193461, and the Breast Cancer Research Foundation. K.J.P. is supported by NIH grants CA143803, CA163124, CA093900 and CA143055. D.P. is supported by the European Research Council (ERC-617457- PHYLOCANCER), the Spanish Ministry of Economy and Competitiveness (BFU2015-63774-P) and the Education, Culture and University Development Department of the Galician Government. K.S.A. is supported in part by the Breast Cancer Research Foundation and NCI R21CA196460. C.S. is supported by the Royal Society, Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169), NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council (THESEUS) and Marie Curie Network PloidyNet. T.A.G. is a Cancer Research UK fellow and a Wellcome Trust funded Investigator. E.S.H. is supported by R01 CA185138-01 and W81XWH-14-1-0473. M.Gerlinger is supported by Cancer Research UK and The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. M.Ge., M.Gr., Y.Y., and A.So. were also supported in part by the Wellcome Trust [105104/Z/14/Z]. J.D.S. holds the Edward B. Clark, MD Chair in Pediatric Research, and is supported by the Primary Children's Hospital (PCH) Pediatric Cancer Research Program, funded by the Intermountain Healthcare Foundation and the PCH Foundation. A.S. is supported by the Chris Rokos Fellowship in Evolution and Cancer. Y.Y. is a Cancer Research UK fellow and supported by The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. E.S.H. was supported in part by PCORI grants 1505–30497 and 1503–29572, NIH grants R01 CA185138, T32 CA093245, and U10 CA180857, CDMRP Breast Cancer Research Program Award BC132057, a CRUK Grand Challenge grant, and the Breast Cancer Research Foundation. A.R.A.A. was funded in part by NIH grant U01CA151924. A.R.A.A., R.G. and J.S.B. were funded in part by NIH grant U54CA193489