Identification of transcriptional regulatory networks specific to pilocytic astrocytoma.

BackgroundPilocytic Astrocytomas (PAs) are common low-grade central nervous system malignancies for which few recurrent and specific genetic alterations have been identified. In an effort to better understand the molecular biology underlying the pathogenesis of these pediatric brain tumors, we performed higher-order transcriptional network analysis of a large gene expression dataset to identify gene regulatory pathways that are specific to this tumor type, relative to other, more aggressive glial or histologically distinct brain tumours.MethodsRNA derived from frozen human PA tumours was subjected to microarray-based gene expression profiling, using Affymetrix U133Plus2 GeneChip microarrays. This data set was compared to similar data sets previously generated from non-malignant human brain tissue and other brain tumour types, after appropriate normalization.ResultsIn this study, we examined gene expression in 66 PA tumors compared to 15 non-malignant cortical brain tissues, and identified 792 genes that demonstrated consistent differential expression between independent sets of PA and non-malignant specimens. From this entire 792 gene set, we used the previously described PAP tool to assemble a core transcriptional regulatory network composed of 6 transcription factor genes (TFs) and 24 target genes, for a total of 55 interactions. A similar analysis of oligodendroglioma and glioblastoma multiforme (GBM) gene expression data sets identified distinct, but overlapping, networks. Most importantly, comparison of each of the brain tumor type-specific networks revealed a network unique to PA that included repressed expression of ONECUT2, a gene frequently methylated in other tumor types, and 13 other uniquely predicted TF-gene interactions.ConclusionsThese results suggest specific transcriptional pathways that may operate to create the unique molecular phenotype of PA and thus opportunities for corresponding targeted therapeutic intervention. Moreover, this study also demonstrates how integration of gene expression data with TF-gene and TF-TF interaction data is a powerful approach to generating testable hypotheses to better understand cell-type specific genetic programs relevant to cancer

Health visitors’ perception of their role in the universal childhood immunisation programme and their communication strategies with parents

Aim: This study explored health visitors’ perception of their role in the universal childhood immunisation programme with particular emphasis on influencing factors and communication strategies. Background: The majority of parents’ consent to immunisation, but some find decision-making in this area difficult and have unmet information needs. In the United Kingdom, health visitors routinely provide immunisation information for parents, whereas general practitioners (GPs) and practice nurses tend to administer vaccines and respond to parents/carers’ questions. Research has investigated health professionals’ views and knowledge about immunisation, but less is understood about health visitors’ role and how they communicate with parents. Method: Following the Local Research Ethics and Research Governance permissions, all health visitors (n5120) working in one county in the United Kingdom were invited to participate in the study. Semistructured interviews (n522) were undertaken using a prompt guide. The interviews were transcribed verbatim. Thematic analysis using an iterative approach was used to explore the data facilitated by NVIVOTM software. Findings: Five themes emerged from the interviews. These were health visitors’professional role; identity and perceived barriers and communication strategies, parents’ right to choose, confidence in measles, mumps, and rubella (MMR) vaccination and communicating with migrant families about immunisation. There were differences between the health visitors in their perceptions of their roles, skills and knowledge and communication strategies. Health visitors perceived that GPs and practice nurses took a paternalistic approach to the provision of immunisation information, while they used a parental decision making model. Health visitors reported a loss of professional confidence following the MMR crisis. Conclusion: Given the evidence that some parents find it difficult to gain the information they need about immunisation and health visitors’ acknowledgement that their usual communication models were not effective during the MMR crisis, we feel specific communication skills training is needed to enable health professionals to provide parents with appropriate decision support

Linkages among runoff, dissolved organic carbon, and the stable oxygen isotope composition of seawater and other water mass indicators in the Arctic Ocean

Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 110 (2005): G02013, doi:10.1029/2005JG000031.Concentrations of dissolved organic carbon (DOC) and δ18O values have been determined following sampling of runoff from a number of major arctic rivers, including the Ob, Yenisey, Lena, Kolyma, Mackenzie and Yukon in 2003-2004. These data are considered in conjunction with marine data for DOC, δ18O values, nutrients, salinity, and fluorometric indicators of DOC that were obtained as part of the Shelf-Basin Interactions program at the continental shelf-basin boundary of the Chukchi and Beaufort Seas. These marine data indicate that the freshwater component is most likely derived from regional sources, such as the Mackenzie, the Bering Strait inflow and possibly eastern Siberian rivers, including the Kolyma, or the Lena but not rivers further west in the Eurasian arctic. Contributions of freshwater from melted sea ice to marine surface waters appeared to be insignificant over annual cycles compared to runoff, although on a seasonal basis, freshwater from melted sea ice was locally dominant following a major sea-ice retreat into the Canada Basin in 2002. DOC concentrations were correlated with the runoff fraction, with an apparent meteoric water DOC concentration of 174 ± 1 μM (standard error). This concentration is lower than the flow-weighted concentrations measured at river mouths of the five largest Arctic rivers (358 to 917 μM), indicating that removal of terrigenous DOC during transport through estuaries, shelves and in the deep basin. DOC data indicate that flow-weighted concentrations in the two largest North American arctic rivers, the Yukon (625μM) and the Mackenzie (382 μM), are lower than in the three largest Eurasian arctic rivers, the Ob (825 μM), the Yenesey (858 μM) and the Lena (917 μM). A fluorometric indicator of chromophoric dissolved organic matter (CDOM) that has provided estimates of terrigenous DOC concentrations in the Eurasian Arctic was not correlated with DOC concentrations in the Amerasian marine waters studied, except below the upper Arctic Ocean halocline. Nutrient distributions and concentrations as well as derived nutrient ratios suggest the CDOM fluorometer may be responding to the release of chromophoric materials from continental shelf sediments. Shipboard incubation experiments with undisturbed sediment cores indicate that continental shelf sediments on the Bering and Chukchi Sea shelves are likely to be a net source of DOC to the Arctic Ocean.The PARTNERS and SBI projects have been supported by the Office of Polar Programs of the U.S. National Science Foundation

Identifying and prioritising unanswered research questions for people with hyperacusis: James Lind Alliance Hyperacusis Priority Setting Partnership

Objective To determine research priorities in hyperacusis that key stakeholders agree are the most important. Design/setting A priority setting partnership using two international surveys, and a UK prioritisation workshop, adhering to the six-staged methodology outlined by the James Lind Alliance. Participants People with lived experience of hyperacusis, parents/carers, family and friends, educational professionals and healthcare professionals who support and/or treat adults and children who experience hyperacusis, including but not limited to surgeons, audiologists, psychologists and hearing therapists. Methods The priority setting partnership was conducted from August 2017 to July 2018. An international identification survey asked respondents to submit any questions/uncertainties about hyperacusis. Uncertainties were categorised, refined and rephrased into representative indicative questions using thematic analysis techniques. These questions were verified as ‘unanswered’ through searches of current evidence. A second international survey asked respondents to vote for their top 10 priority questions. A shortlist of questions that represented votes from all stakeholder groups was prioritised into a top 10 at the final prioritisation workshop (UK). Results In the identification survey, 312 respondents submitted 2730 uncertainties. Of those uncertainties, 593 were removed as out of scope, and the remaining were refined into 85 indicative questions. None of the indicative questions had already been answered in research. The second survey collected votes from 327 respondents, which resulted in a shortlist of 28 representative questions for the final workshop. Consensus was reached on the top 10 priorities for future research, including identifying causes and underlying mechanisms, effective management and training for healthcare professionals. Conclusions These priorities were identified and shaped by people with lived experience, parents/carers and healthcare professionals, and as such are an essential resource for directing future research in hyperacusis. Researchers and funders should focus on addressing these priorities.Additional co-authors: Tracey Pollard, Helen Henshaw, Toto A Gronlund, Derek J Hoar

Conducting Environmental Health Research in the Arabian Middle East: Lessons Learned and Opportunities

Background: The Arabian Gulf nations are undergoing rapid economic development, leading to major shifts in both the traditional lifestyle and the environment. Although the pace of change is brisk, there is a dearth of environmental health research in this region

Indoor Air Pollutants and Health in the United Arab Emirates

Background: Comprehensive global data on the health effects of indoor air pollutants are lacking. There are few large population-based multi–air pollutant health assessments. Further, little is known about indoor air health risks in the Middle East, especially in countries undergoing rapid economic development

The oestrogen receptor alpha-regulated lncRNA NEAT1 is a critical modulator of prostate cancer

The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription

Collision tumors revealed by prospectively assessing subtype-defining molecular alterations in 904 individual prostate cancer foci.

BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063)

Allelic polymorphism in the T cell receptor and its impact on immune responses

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01 public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501 revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection

Randomized controlled trial and economic evaluation of nurse-led group support for young mothers during pregnancy and the first year postpartum versus usual care

Background Child maltreatment is a significant public health problem. Group Family Nurse Partnership (gFNP) is a new intervention for young, expectant mothers implemented successfully in pilot studies. This study was designed to determine the effectiveness and cost effectiveness of gFNP in reducing risk factors for maltreatment with a potentially vulnerable population. Methods A multi-site randomized controlled parallel-arm trial and prospective economic evaluation was conducted, with allocation via remote randomization (minimization by site, maternal age group) to gFNP or usual care. Participants were expectant mothers aged <20 with at least one live birth, or 20–24 with no live births and with low educational qualifications. Data from maternal interviews at baseline and when infants were two, six and 12 months, and video recording at 12 months, were collected by researchers blind to allocation. Cost information came from weekly logs completed by gFNP family nurses and other service delivery data reported by participants. Primary outcomes measured at 12 months were parenting attitudes (Adult- Adolescent Parenting Index, AAPI-2) and maternal sensitivity (CARE index). The economic evaluation was conducted from a UK NHS and personal social services perspective with cost-effectiveness expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. Main analyses were intention to treat with additional complier average causal effects (CACE) analyses. Results Between August 2013 and September 2014, 492 names of potential participants were received of whom 319 were eligible and 166 agreed to take part, 99 randomly assigned to receive gFNP and 67 to usual care. There were no between-arms differences in AAPI-2 total (7·5/10 in both, SE 0.1), difference adjusted for baseline, site and maternal age-group 0·06 (95% CI -0·15 to 0·28, p=0·59) or CARE Index (intervention 4·0 (SE 0·3); control 4·7(SE 0·4); difference adjusted for site and maternal age-group -0·68; 95% CI -1·62 to 0·16, p=0·25) scores. The probability that gFNP is cost-effective based on the QALY measure did not exceed 3%. Conclusions The trial did not support gFNP as a means of reducing the risk of child maltreatment in this population but slow recruitment adversely affected group size and consequently delivery of the intervention