Charting differentially methylated regions in cancer with Rocker-meth

Matteo Benelli et al. present Rocker-meth, a new Hidden Markov Model (HMM)-based method, to robustly identify differentially methylated regions (DMRs). They use Rocker-meth to analyse more than 6000 methylation profiles across 14 cancer types, providing a catalog of tumor-specific and shared DMRs

Erratum to 'Core Biopsies from Prostate Cancer Patients in Active Surveillance Protocols Harbor PTEN and MYC Alterations'[European Urology Oncology 2 (2019) 277-285].

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A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth

Somatic mutations activating MAPK/PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumour based on somatic expression of oncogenes that activate MAPK/PI3K signalling in neural progenitor cells. HRASV12 was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho‑(p)ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of a 8-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide TCGA sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP may be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant active YAP (YAPS5A) and HRASV12 abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours may originate from the same somatic mutations activating oncogenes and established that YAP activation is a hallmark of malignant brain tumours

DIAPH3 Governs the Cellular Transition to the Amoeboid Tumour Phenotype

Therapies for most malignancies are generally ineffective once metastasis occurs. While tumour cells migrate through tissues using diverse strategies, the signalling networks controlling such behaviours in human tumours are poorly understood. Here we define a role for the Diaphanous-related formin-3 (DIAPH3) as a non-canonical regulator of metastasis that restrains conversion to amoeboid cell behaviour in multiple cancer types. The DIAPH3 locus is close to RB1, within a narrow consensus region of deletion on chromosome 13q in prostate, breast and hepatocellular carcinomas. DIAPH3 silencing in human carcinoma cells destabilized microtubules and induced defective endocytic trafficking, endosomal accumulation of EGFR, and hyperactivation of EGFR/MEK/ERK signalling. Silencing also evoked amoeboid properties, increased invasion and promoted metastasis in mice. In human tumours, DIAPH3 down-regulation was associated with aggressive or metastatic disease. DIAPH3-silenced cells were sensitive to MEK inhibition, but showed reduced sensitivity to EGFR inhibition. These findings have implications for understanding mechanisms of metastasis, and suggest that identifying patients with chromosomal deletions at DIAPH3 may have prognostic value

CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RNA alternative splicing

Disruptive mutations in the chromodomain helicase DNA-binding protein 8 gene (CHD8) have been recurrently associated with autism spectrum disorders (ASDs). Here we investigated how chromatin reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes and correlates with altered alternative splicing patterns of 462 genes implicated in ‘regulation of RNA splicing’ and ‘mRNA catabolic process’. Mass spectrometry analysis uncovered a novel interaction between CHD8 and the splicing regulator heterogeneous nuclear ribonucleoprotein L (hnRNPL), providing the first mechanistic insights to explain the CHD8 suppression-derived splicing phenotype, partly implicating SETD2, a H3K36me3 methyltransferase. In summary, our results point toward broad molecular consequences of CHD8 suppression, entailing altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD

Phenology, Seasonal Abundance, and Host-Plant Association of Spittlebugs (Hemiptera: Aphrophoridae) in Vineyards of Northwestern Italy

Spittlebugs (Hemiptera: Aphrophoridae) are the vectors of the bacterium Xylella fastidiosa (Xf) in Europe. Xf may cause severe epidemics in cultivated plants, including grapevines. To assess the threat represented by the bacterium to grapevines, detailed information on the vectors’ phenology, density, and ecology in vineyards is needed. The aim of the present work was to describe spittlebug diversity, phenology, and host-plant association in the vineyard agroecosystem. Two separate field surveys of nymphal and adult spittlebug populations, i.e., a two-year survey of a single site and a one-year survey of three sites, were performed in vineyards of northwestern Italy in three consecutive years. Philaenus spumarius was the most common species, reaching average nymph densities on herbaceous cover up to 60–130 nymphs/m2. Adults were sampled on grapevines from May to September, with a peak in June (up to 0.43 insects/sweep). Herbaceous cover was colonized after egg hatching and in late summer for oviposition, while wild woody hosts represented a refuge during summer. The results show that spittlebugs can reach high population levels in vineyards, at least in the areas where the ground is covered by herbaceous plants for the whole season and the use of insecticides is moderate. The extended presence of P. spumarius adults on grapevines represents a serious risk factor for the spread of Xf. The scenarios of Xf establishment in vineyards in northwestern Italy and Europe are discussed in relation to the abundance, phenology, and plant association of spittlebugs

The infrared spectrum of ortho-enstatite from reflectance experiments and first-principle simulations

Infrared (IR) spectra provide a rich amount of information concerning chemical composition, lattice structure, size and shape of circumstellar dust. Accurate reference data are then required for the analysis of the various detected components. This study provides the IR characterization of one of the most frequently observed compounds, MgSiO3 ortho-enstatite, and shows that IR experiments and ab initio techniques can be used synergically to obtain high-quality data concerning crystalline materials. The IR reflectance spectrum of synthetic ortho-enstatite was collected and compared to ab initio results (Gaussian-type basis set, PBE0 hybrid density functional theory (DFT) functional). An excellent agreement is observed both for vibrational frequencies (ν) and intensities, the latter estimated through the oscillator strength. The mean absolute difference between experimental and calculated ν is of the order of 7–8 cm−1 (43 out of 65 peaks differ by less than 10 cm−1, only four peaks differ by 15–19 cm−1). The static dielectric tensor and its components (electronic and ionic contributions) were measured and compared to calculated data: differences are in the 2–5 per cent range