Discovery of new methylation markers to improve screening for cervical intraepithelial neoplasia grade 2/3

Background: Assessment of DNA promoter methylation markers in cervical scrapings for the detection of cervical intraepithelial neoplasia (CIN) and cervical cancer is feasible, but finding methylation markers with both high sensitivity as well as high specificity remains a challenge. In this study, we aimed to identify new methylation markers for the detection of high-grade CIN (CIN2/3 or worse, CIN2+) by using innovative genome-wide methylation analysis (MethylCap-seq). We focused on diagnostic performance of methylation markers with high sensitivity and high specificity considering any methylation level as positive. Results: MethylCap-seq of normal cervices and CIN2/3 revealed 176 differentially methylated regions (DMRs) comprising 164 genes. After verification and validation of the 15 best discriminating genes with methylation-specific PCR (MSP), 9 genes showed significant differential methylation in an independent cohort of normal cervices versus CIN2/3 lesions (p < 0.05). For further diagnostic evaluation, these 9 markers were tested with quantitative MSP (QMSP) in cervical scrapings from 2 cohorts: (1) cervical carcinoma versus healthy controls and (2) patients referred from population-based screening with an abnormal Pap smear in whom also HPV status was determined. Methylation levels of 8/9 genes were significantly higher in carcinoma compared to normal scrapings. For all 8 genes, methylation levels increased with the severity of the underlying histological lesion in scrapings from patients referred with an abnormal Pap smear. In addition, the diagnostic performance was investigated, using these 8 new genes and 4 genes (previously identified by our group: C13ORF18, JAM3, EPB41L3, and TERT). In a triage setting (after a positive Pap smear), sensitivity for CIN2+ of the best combination of genes (C13ORF18/JAM3/ANKRD18CP) (74 %) was comparable to hrHPV testing (79 %), while specificity was significantly higher (76 % versus 42 %, p <= 0.05). In addition, in hrHPV-positive scrapings, sensitivity and specificity for CIN2+ of this best-performing combination was comparable to the population referred with abnormal Pap smear. Conclusions: We identified new CIN2/3-specific methylation markers using genome-wide DNA methylation analysis. The diagnostic performance of our new methylation panel shows higher specificity, which should result in prevention of unnecessary colposcopies for women referred with abnormal cytology. In addition, these newly found markers might be applied as a triage test in hrHPV-positive women from population-based screening. The next step before implementation in primary screening programs will be validation in population-based cohorts

Geometric Satake, Springer correspondence, and small representations

For a simply-connected simple algebraic group $G$ over \C, we exhibit a subvariety of its affine Grassmannian that is closely related to the nilpotent cone of $G$, generalizing a well-known fact about $GL_n$. Using this variety, we construct a sheaf-theoretic functor that, when combined with the geometric Satake equivalence and the Springer correspondence, leads to a geometric explanation for a number of known facts (mostly due to Broer and Reeder) about small representations of the dual group.Comment: Version 2: minor revisions, 33 page

Marine spatial planning: risk or opportunity for fisheries in the North Sea?

The North Sea is one of the busiest marine areas in the world. It is also a major fisheries ground. Bordered by seven countries with their own spatial uses and claims, the stage is set for complex and demanding governance challenges. Recent decades have also seen user groups multiply, competition for space and resources increase, and the pressure on the marine environment and its living natural resources grow. As governments strive to balance conservation and economic development needs, they also have to deal with inter-as well as intra-national user conflicts. Marine Spatial Planning (MSP) has arrived as a new approach to these issues. It is argued that for North Sea fishing people and their communities MSP holds risks as well as opportunities, depending on which institutions are formed and what role they are allowed to play in the planning process

Local Adaptation of Aboveground Herbivores towards Plant Phenotypes Induced by Soil Biota

Background: Soil biota may trigger strong physiological responses in plants and consequently induce distinct phenotypes. Plant phenotype, in turn, has a strong impact on herbivore performance. Here, we tested the hypothesis that aboveground herbivores are able to adapt to plant phenotypes induced by soil biota. Methodology and Principal Findings: We bred spider mites for 15 generations on snap beans with three different belowground biotic interactions: (i) no biota (to serve as control), (ii) arbuscular mycorrhizal fungi and (ii) root-feeding nematodes. Subsequently, we conducted a reciprocal selection experiment using these spider mites, which had been kept on the differently treated plants. Belowground treatments induced changes in plant biomass, nutrient composition and water content. No direct chemical defence through cyanogenesis was detected in any of the plant groups. Growth rates of spider mites were higher on the ecotypes on which they were bred for 15 generations, although the statistical significance disappeared for mites from the nematode treatment when corrected for all multiple comparisons. Conclusion/Significance: These results demonstrate that belowground biota may indeed impose selection on the aboveground insect herbivores mediated by the host plant. The observed adaptation was driven by variable quantitativ

Preventive drugs in the last year of life of older adults with cancer: Is there room for deprescribing?

BACKGROUND: The continuation of preventive drugs among older patients with advanced cancer has come under scrutiny because these drugs are unlikely to achieve their clinical benefit during the patients' remaining lifespan. METHODS: A nationwide cohort study of older adults (those aged ≥65 years) with solid tumors who died between 2007 and 2013 was performed in Sweden, using routinely collected data with record linkage. The authors calculated the monthly use and cost of preventive drugs throughout the last year before the patients' death. RESULTS: Among 151,201 older persons who died with cancer (mean age, 81.3 years [standard deviation, 8.1 years]), the average number of drugs increased from 6.9 to 10.1 over the course of the last year before death. Preventive drugs frequently were continued until the final month of life, including antihypertensives, platelet aggregation inhibitors, anticoagulants, statins, and oral antidiabetics. Median drug costs amounted to $1482 (interquartile range [IQR],$700-$2896]) per person, including$213 (IQR, $77-$490) for preventive therapies. Compared with older adults who died with lung cancer (median drug cost, $205; IQR,$61-$523), costs for preventive drugs were higher among older adults who died with pancreatic cancer (adjusted median difference,$13; 95% confidence interval, $5-$22) or gynecological cancers (adjusted median difference, $27; 95$18-$36). There was no decrease noted with regard to the cost of preventive drugs throughout the last year of life. CONCLUSIONS: Preventive drugs commonly are prescribed during the last year of life among older adults with cancer, and often are continued until the final weeks before death. Adequate deprescribing strategies are warranted to reduce the burden of drugs with limited clinical benefit near the end of life

E-Cadherin Acts as a Regulator of Transcripts Associated with a Wide Range of Cellular Processes in Mouse Embryonic Stem Cells

We have recently shown that expression of the cell adhesion molecule E-cadherin is required for LIF-dependent pluripotency of mouse embryonic stem (ES) cells.In this study, we have assessed global transcript expression in E-cadherin null (Ecad-/-) ES cells cultured in either the presence or absence of LIF and compared these to the parental cell line wtD3.We show that LIF has little effect on the transcript profile of Ecad-/- ES cells, with statistically significant transcript alterations observed only for Sp8 and Stat3. Comparison of Ecad-/- and wtD3 ES cells cultured in LIF demonstrated significant alterations in the transcript profile, with effects not only confined to cell adhesion and motility but also affecting, for example, primary metabolic processes, catabolism and genes associated with apoptosis. Ecad-/- ES cells share similar, although not identical, gene expression profiles to epiblast-derived pluripotent stem cells, suggesting that E-cadherin expression may inhibit inner cell mass to epiblast transition. We further show that Ecad-/- ES cells maintain a functional β-catenin pool that is able to induce β-catenin/TCF-mediated transactivation but, contrary to previous findings, do not display endogenous β-catenin/TCF-mediated transactivation. We conclude that loss of E-cadherin in mouse ES cells leads to significant transcript alterations independently of β-catenin/TCF transactivation

Impact Factor: outdated artefact or stepping-stone to journal certification?

A review of Garfield's journal impact factor and its specific implementation as the Thomson Reuters Impact Factor reveals several weaknesses in this commonly-used indicator of journal standing. Key limitations include the mismatch between citing and cited documents, the deceptive display of three decimals that belies the real precision, and the absence of confidence intervals. These are minor issues that are easily amended and should be corrected, but more substantive improvements are needed. There are indications that the scientific community seeks and needs better certification of journal procedures to improve the quality of published science. Comprehensive certification of editorial and review procedures could help ensure adequate procedures to detect duplicate and fraudulent submissions.Comment: 25 pages, 12 figures, 6 table

Identification of QTLs controlling gene expression networks defined a priori

BACKGROUND: Gene expression microarrays allow the quantification of transcript accumulation for many or all genes in a genome. This technology has been utilized for a range of investigations, from assessments of gene regulation in response to genetic or environmental fluctuation to global expression QTL (eQTL) analyses of natural variation. Current analysis techniques facilitate the statistical querying of individual genes to evaluate the significance of a change in response, also known as differential expression. Since genes are also known to respond as groups due to their membership in networks, effective approaches are needed to investigate transcriptome variation as related to gene network responses. RESULTS: We describe a statistical approach that is capable of assessing higher-order a priori defined gene network response, as measured by microarrays. This analysis detected significant network variation between two Arabidopsis thaliana accessions, Bay-0 and Shahdara. By extending this approach, we were able to identify eQTLs controlling network responses for 18 out of 20 a priori-defined gene networks in a recombinant inbred line population derived from accessions Bay-0 and Shahdara. CONCLUSION: This approach has the potential to be expanded to facilitate direct tests of the relationship between phenotypic trait and transcript genetic architecture. The use of a priori definitions for network eQTL identification has enormous potential for providing direction toward future eQTL analyses