Comprehensive interrogation of gene lists from genome-scale cancer screens with oncoEnrichR

Genome-scale screening experiments in cancer produce long lists of candidate genes that require extensive interpretation for biological insight and prioritization for follow-up studies. Interrogation of gene lists frequently represents a significant and time-consuming undertaking, in which experimental biologists typically combine results from a variety of bioinformatics resources in an attempt to portray and understand cancer relevance. As a means to simplify and strengthen the support for this endeavor, we have developed oncoEnrichR, a flexible bioinformatics tool that allows cancer researchers to comprehensively interrogate a given gene list along multiple facets of cancer relevance. oncoEnrichR differs from general gene set analysis frameworks through the integration of an extensive set of prior knowledge specifically relevant for cancer, including ranked gene-tumor type associations, literature-supported proto-oncogene and tumor suppressor gene annotations, target druggability data, regulatory interactions, synthetic lethality predictions, as well as prognostic associations, gene aberrations and co-expression patterns across tumor types. The software produces a structured and user-friendly analysis report as its main output, where versions of all underlying data resources are explicitly logged, the latter being a critical component for reproducible science. We demonstrate the usefulness of oncoEnrichR through interrogation of two candidate lists from proteomic and CRISPR screens. oncoEnrichR is freely available as a web-based service hosted by the Galaxy platform ( https://oncotools.elixir.no ), and can also be accessed as a stand-alone R package ( https://github.com/sigven/oncoEnrichR ).     

Trends in cancer incidence by socioeconomic deprivation in Germany in 2007 to 2018: An ecological registry-based study

Age-standardized cancer incidence has decreased over the last years for many cancer sites in developed countries. Whether these trends led to narrowing or widening socioeconomic inequalities in cancer incidence is unknown. Using cancer registry data covering 48 million inhabitants in Germany, the ecological association between age-standardized total and site specific (colorectal, lung, prostate and breast) cancer incidence in 2007 to 2018 and a deprivation index on district level (aggregated to quintiles) was investigated. Incidence in the most and least deprived districts were compared using Poisson models. Average annual percentage changes (AAPCs) and differences in AAPCs between deprivation quintiles were assessed using Joinpoint regression analyses. Age-standardized incidence decreased strongly between 2007 and 2018 for total cancer and all cancer sites (except female lung cancer), irrespective of the level of deprivation. However, differences in the magnitude of trends across deprivation quintiles resulted in increasing inequalities over time for total cancer, colorectal and lung cancer. For total cancer, the incidence rate ratio between the most and least deprived quintile increased from 1.07 (95% confidence interval: 1.01-1.12) to 1.23 (1.12-1.32) in men and from 1.07 (1.01-1.13) to 1.20 (1.14-1.26) in women. Largest inequalities were observed for lung cancer with 82% (men) and 88% (women) higher incidence in the most vs the least deprived regions in 2018. The observed increase in inequalities in cancer incidence is in alignment with trends in inequalities in risk factor prevalence and partly utilization of screening. Intervention programs targeted at socioeconomically deprived and urban regions are highly needed.     

Standardisierte Kontrastmittelsonographie (CEUS) in der klinischen Akut- und Notfallmedizin sowie Intensivmedizin (CEUS-Akut)

Die Anaesthesiologie -     

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Objectives

Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC.

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO-grade II—Report from the German/Swiss SIOP-LGG 2004 cohort

Reports on pediatric low-grade diffuse glioma WHO-grade II (DG2) suggest an impaired survival rate, but lack conclusive results for genetically defined DG2-entities. We analyzed the natural history, treatment and prognosis of DG2 and investigated which genetically defined sub-entities proved unfavorable for survival. Within the prospectively registered, population-based German/Swiss SIOP-LGG 2004 cohort 100 patients (age 0.8-17.8 years, 4% neurofibromatosis [NF1]) were diagnosed with a DG2. Following biopsy (41%) or variable extent of resection (59%), 65 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemotherapy (n = 18) or radiotherapy (n = 17). Multiple lines of salvage treatment were necessary for 19/35 patients. Five years event-free survival dropped to 0.44, while 5 years overall survival was 0.90 (median observation time 8.3 years). Extensive genetic profiling of 65/100 DG2 identified Histone3-K27M-mutation in 4, IDH1-mutation in 11, BRAF-V600-mutation in 12, KIAA1549-BRAF-fusions in 6 patients, while the remaining 32 tumor tissues did not show alterations of these genes. Progression to malignant glioma occurred in 12 cases of all genetically defined subgroups within a range of 0.5 to 10.8 years, except for tumors carrying KIAA1549-BRAF-fusions. Histone3-K27M-mutant tumors proved uniformly fatal within 0.6 to 2.4 years. The current LGG treatment strategy seems appropriate for all DG2-entities, with the exemption of Histone3-K27M-mutant tumors that require a HGG-related treatment strategy. Our data confirm the importance to genetically define pediatric low-grade diffuse gliomas for proper treatment decisions and risk assessment.     

End-of-life care for glioma patients; the caregivers’ perspective

Journal of Neuro-Oncology - Gliomas are primary brain tumors with a life-limiting course of disease, and the last weeks of life are often characterized by neurological deficits that affect...     

Is there an association between overweight/obesity and dental implant complications? A systematic review and meta-analysis

The aim of this systematic review was to test the following hypotheses: (1) that there is no difference in implant survival rate between individuals with overweight or obesity and those who are within the ideal weight range; (2) that there are no differences between these groups regarding indicators of peri-implant health. Two independent reviewers performed a literature search of the PubMed/MEDLINE, Scopus, and Cochrane Library databases for studies published up to April 1, 2018. A meta-analysis was performed to determine the risk difference for implant failure and mean difference for marginal bone loss, probing depth, and bleeding on probing. Six studies were selected for review, involving a total of 746 patients with 986 implants: 609 in overweight or obese individuals and 377 in individuals within the ideal weight range. The findings of this systematic review indicate that the first hypothesis should be accepted, since no statistically significant difference in implant survival rate was found between individuals with overweight/obesity and those within the ideal weight range (P = 0.64). The second hypothesis was rejected, as the review indicated a difference in marginal bone loss (P < 0.00001), probing depth (P < 0.00001), and bleeding around dental implants (P < 0.00001).     

Risikokommunikation politikberatender Wissenschaftsorganisationen: Ein Themenaufriss am Beispiel des Bundesinstituts für Risikobewertung

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Regulierungswissenschaftliche Organisationen wie das Bundesinstitut für Risikobewertung (BfR) sehen sich in ihrer...     

A multitaxa assessment of the effectiveness of agri-environmental schemes for biodiversity management

Agri-environmental schemes (AES) aim to restore biodiversity and biodiversity-mediated ecosystem services in landscapes impoverished by modern agriculture. However, a systematic, empirical evaluation of different AES types across multiple taxa and functional groups is missing. Within one orthogonal design, we studied sown flowering AES types with different temporal continuity, size, and landscape context and used calcareous grasslands as seminatural reference habitat. We measured species richness of 12 taxonomic groups (vascular plants, cicadas, orthopterans, bees, butterflies, moths, hoverflies, flower visiting beetles, parasitoid wasps, carabid beetles, staphylinid beetles, and birds) representing 5 trophic levels. A total of 54,955 specimens were identified using traditional taxonomic methods, and bulk arthropod samples were identified through DNA metabarcoding, resulting in a total of 1,077 and 2,110 taxa, respectively. Species richness of most taxonomic groups, as well as multidiversity and richness of pollinators, increased with temporal continuity of AES types. Some groups responded to size and landscape context, but multidiversity and richness of pollinators and natural enemies were not affected. AES flowering fields supported different species assemblages than calcareous grasslands, but assemblages became more similar to those in seminatural grasslands with increasing temporal continuity. Our results indicate that AES flowering fields and seminatural grasslands function synergistically. Flowering fields support biodiversity even when they are relatively small and in landscapes with few remaining seminatural habitats. We therefore recommend a network of smaller, temporally continuous AES flowering fields of different ages, combined with permanent seminatural grasslands, to maximize benefits for biodiversity conservation and ecosystem service delivery in agricultural landscapes.

Human societies are facing a worldwide loss of biodiversity with alarming declines of insect diversity in temperate agricultural landscapes (1, 2). This loss of biodiversity is jeopardizing agricultural production as important ecosystem services ensuring crop yields are directly driven by biodiversity (3). Biodiversity, however, requires suitable habitats for species to persist, forage, nest, reproduce, and hibernate (4, 5). This challenge has been recognized and agri-environmental schemes (AES) have been introduced in the European Union and other regions to reverse biodiversity declines, to restore functional diversity, and to harness the benefits of ecosystem services, like pollination and pest control, in agricultural landscapes (6–8).An important component of AES to fulfill these goals is the establishing of habitats that provide limiting resources, such as food and shelter for a broad range of organisms. Typically, farmers are financially compensated on a per area basis, but the effectiveness of schemes is often unclear. Thus, compensations might not direct farmers’ decisions among different AES to the ecologically most meaningful ones (7). A variety of different habitats are created as AES, ranging from hedgerows to sown flower strips or flowering fields, with the latter being widely used due to their flexible applicability and public appreciation (4). Recent assessments, however, found that overall, European AES are not fulfilling their goals (6, 9). Particularly, the value of AES for securing biodiversity is under debate (10, 11). Beneficial effects previously reported focused on single taxonomic or trophic levels or ecosystem services and varied among study designs, taxa, or services assessed (12–14). Conclusive multitaxa approaches assessing potential services and disservices in one design are missing (8). Furthermore, it is unclear how different properties of AES habitats (e.g., their temporal continuity or size) and varying landscape context affect biodiversity across multiple taxonomic groups.Temporal continuity is an important factor affecting biodiversity. Higher temporal continuity increases heterogeneity within a habitat and creates niches for more species (15, 16). Temporal continuity also enables weak dispersers and higher tropic levels to colonize a habitat, with the latter being dependent on established populations of lower trophic levels (15). In AES habitats, the influence and the effects of temporal continuity have so far been neglected. Newly established flowering fields were found to be more attractive to pollinators than older flowering fields, but pollination services in adjacent fields peak 2 y after initial sowing (14, 17). Older AES habitats could potentially also benefit rare and endangered species with specific habitat requirements, if species assemblages in AES habitats change toward those in permanent species-rich seminatural grasslands with time or increased temporal continuity (18).Apart from temporal continuity, size might be an important predictor for the conservation value of AES habitats. Increasing habitat size leads to an increased species richness as it is accompanied with the establishment of larger, more stable populations and allows higher trophic levels to persist (19–21). It is unclear whether biodiversity in a landscape benefits more from few large habitats or a network of many small habitats (22, 23). Relationships between size and species richness might therefore be essential for the planning and strategic placement of AES habitats.Source habitats for biodiversity are needed in agricultural landscapes to build up local populations in newly established AES habitats from regional species pools (24). Seminatural habitats embedded in agricultural landscapes have been shown to support farmland diversity (25, 26), and thus AES habitats in complex landscapes with high proportions of seminatural habitats potentially host the highest diversity.Here, we investigate the effects of AES differing in temporal continuity, size, and surrounding landscape context over several years on multiple taxonomic groups within one study design. Different types of flowering fields are commonly established by farmers as part of AES to provide additional flower resources. These fields are sown with seed mixtures adapted to local soil properties and taken from regional species pools. After a certain timespan, often varying from 1 to 10 y, flowering fields are returned to crop production. The studied flowering fields differed in temporal continuity from: 1) Newly sown on arable land, over 2) refreshed (i.e., flower fields resown after 5 y) to 3) continuous, 6-y-old flowering fields. Species-rich calcareous grasslands were used as permanent control (Fig. 1 and Table 1). Calcareous grasslands are seminatural biodiversity hotspots in Europe and are preserved by low intensive mowing or grazing (27). We investigated species richness in these 4 AES types across 12 taxonomic groups belonging to 5 trophic levels, including pollinators (bees, butterflies, moths, flower visiting beetles, and hoverflies) and natural enemies (parasitoid wasps, carabid beetles, staphylinid beetles, and birds) as providers of important ecosystem services (3). Species were identified by classic taxonomic techniques (vascular plants, orthopterans, bees, butterflies, moths, flower visiting beetles, carabid beetles, staphylinid beetles, and birds) and DNA metabarcoding (cicadas, hoverflies, and parasitoid wasps). Repeated recordings of a subset of four taxonomic groups (plants, orthopterans, bees, and carabid beetles) within 2 y were performed to clarify whether short-term succession changed assemblages in newly established flowering fields toward those in seminatural calcareous grasslands. Apart from analyses for each taxonomic group, we performed a multidiversity analysis by calculating a diversity index across all taxa, pollinators, and natural enemies (28). Our study aims to judge which types of AES fulfill the goal of restoring biodiversity and ecosystem services in agricultural landscapes best, and should therefore be fostered. Such data are urgently needed to build the scientific basis for a successful transition of European Union and global policies to biodiversity-friendly and sustainable crop production.Open in a separate windowFig. 1.Study design on the landscape and site level. Biodiversity across 12 different taxonomic levels (from top to bottom: Vascular plants, orthopterans, cicadas, bees, butterflies, moths, flower visiting beetles, hoverflies, parasitoid wasps, carabid beetles, staphylinid beetles, birds) was recorded using a variety of classic methods (pan traps, pitfall traps, transect walks, light traps combined with taxonomic identification) as well as metabarcoding analyses (using samples collected with Malaise traps). The different types of flowering fields and calcareous grasslands were located along a gradient of temporal continuity (Table 1). All AES types covered independent gradients of seminatural habitat in the surrounding landscape and habitat size (purple, AES; yellow, arable land; light green, seminatural habitat; dark green, forest; gray, urban). Repeated recordings over 2 y were performed for vascular plants, orthopterans, bees, and carabid beetles to assess whether succession shifted assemblages in flowering fields toward those in seminatural calcareous grasslands.Table 1.Differences in temporal continuity