DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity

BACKGROUND: Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. RESULTS: Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13148-022-01406-4

Versuchsbeschrieb und Qualität des frischen Wiesenfutters : Serie Systemvergleich Hohenrain II

Im Systemvergleich Hohenrain II wurden drei Fütterungssysteme auf Basis von frischem Wiesenfutter miteinander verglichen. Dazu wurden von 2014-2016 die zwei Systeme Teilweide mit Eingrasen und reduzierter (EGKF) beziehungsweise erhöhter Kraftfuttergabe (EGKFplus) mit der Vollweide (VW) als Referenzsystem verglichen. Auf dem Gutsbetrieb des BBZN Hohenrain in Luzern wurden drei Herden in je einem Fütterungssystem gehalten. Allen Herden stand dieselbe Futterfläche zur Verfügung. Auch 36 Pilotbetriebe aus dem Schweizer Mittelland beteiligten sich am Projekt und unterstützten über die Teilnahme an Arbeitskreisen die Praxisverknüpfung und den Wissenstransfer. Die höchsten Energiegehalte im Eingrasfutter wurden im Frühjahr erreicht. Diese sind mit den bekannten Tabellenwerten vergleichbar. Gegenüber den Kurzrasenweiden lagen die Gehalte bedeutend tiefer und waren insbesondere über die Sommermonate starken Schwankungen unterworfen. Dies wird auf das Nutzungsstadium und die sommerlichen Witterungseinflüsse zurückgeführt, welche die Verdaulichkeit des Wiesenfutters wesentlich beeinflussen. Analog zur Weide sollten deshalb Entscheidungshilfen entwickelt werden, welche die Praxis bei der Nutzung der Eingrasbestände im optimalen Stadium unterstützen.In Svizzera molte aziende produttrici di latte fanno uso di sostanziali percentuali di foraggio verde nella razione alimentare. Obiettivo di questo progetto è stata la comparazione tra tre sistemi che si basano sull’alimentazione del bestiame con man-gime verde fresco. A tale scopo, tra il 2014 e il 2016, i due sistemi a pascolo parziale con afforaggiamento di erba fresca e apporto di concentrati ridotto (EGKF) o maggiorato (EGKFplus) sono stati messi a confronto, assumendo il pascolo integrale (VW) come sistema di riferimento. Il presente articolo informa sul dispositivo dell’esperimento e sui primi risultati riguardanti il contenuto di energia del foraggio verde fresco. Nell’a-zienda agricola del centro di formazione professionale BBZN di Hohenrain (LU) il bestiame da latte (70 capi) è stato suddiviso in tre mandrie e inserito nei rispettivi sistemi di foraggiamento. Ad ogni mandria è stata messa a disposizione la stessa superficie di terreno per il pascolo o le colture foraggere (12 ha), mentre la media del numero di mucche e la quantità di mangime concen-trato impiegato erano differenziate in base ai diversi sistemi. Anche 36 aziende agricole dell’altopiano svizzero hanno preso parte al progetto, sostenendo la messa in pratica e il trasferimento del sapere tramite la parteci-pazione a gruppi di lavoro. I tenori più alti di energia netta di lattazione (NEL) nel forag-gio verde (MJ/kg SS) sono stati raggiunti in primavera, ed erano paragonabili ai valori delle tabelle di riferimento. I tenori sono risultati essere significativamente inferiori rispetto a quelli del pascolo ad erba corta e sono stati soggetti a forti oscillazioni soprat-tutto nei mesi estivi. Ciò è da ricondurre all’irregolare stadio di maturazione dell’erba al momento della raccolta e alle condizioni metereologiche, che influenzano di molto la digeribilità del foraggio verde. Supporti decisionali alla pratica dell’afforaggiamento di erba fresca potrebbero contribuire a migliorare la situazione.Partial grazing with indoor feeding of fresh grass is an important feeding system for Swiss dairy farms. From 2014 to 2016, three production systems – ‘partial grazing with indoor feeding of fresh grass with reduced (EGKF, 418 kg) and increased concentrate supplementation (EGKFplus; 1161 kg) was compared with full-time grazing (FG) with reduced concentrate supplementation on 36 pilot farms in Switzerland. This article describes the set-up and initial results regarding the energy content of the fresh grass. The seventy-head dairy herd on the BBZN Hohenrain school farm in Lucerne was divided into three sub-herds, each of which was kept in one of the three feeding systems. While all three herds had the same amount of land at their disposal as pasture or foddergrowing land (12 ha), the average number of cows and the quantity of concentrate used differed according to the system. Thirty-six pilot farms in the Swiss Plateau were also involved in the project and gave support by participating in study groups focussing on linking practice and transferring knowledge. The highest NEL contents in grass fodder (MJ/kg DM) were measured in spring. These were comparable with reference values. However, compared to continuous grazing, the contents were significantly lower and, particularly during summer, were subject to strong fluctuations. This is a result of the irregular utilisation stage and the influence of summer weather conditions, both of which significantly impact the digestibility of grass fodder. Decision-making aids to support practitioners with forage harvesting could lead to improvements here

Cut Points and Diffusions in Random Environment

In this article we investigate the asymptotic behavior of a new class of multi-dimensional diffusions in random environment. We introduce cut times in the spirit of the work done by Bolthausen, Sznitman and Zeitouni, see [4], in the discrete setting providing a decoupling effect in the process. This allows us to take advantage of an ergodic structure to derive a strong law of large numbers with possibly vanishing limiting velocity and a central limit theorem under the quenched measure.Comment: 44 pages; accepted for publication in "Journal of Theoretical Probability

Symposium on the Scottish labour market

In the post-war period, up to the late 1960s, Britain enjoyed a modicum of unemployment and government policies which were geared to producing Full Employment were considered a success. It was simple - boost demand and more people would find work. But the mid 1970s the economic regency enjoyed by those advocating demand sided policies fell into disrepute as the OPEC nations raised prices dramatically and brought in a new era of both rising prices and unemployment. The laws of economics, which previously had viewed policy decisions as the choice between lower unemployment and higher inflation were now redundant. Both unemployment and inflation were moving in the same direction. The era of stagflation had begun

Increased DNA methylation variability in type 1 diabetes across three immune effector cell types

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.This work was funded by the EU-FP7 project BLUEPRINT (282510) and the Wellcome Trust (99148). We thank all twins for taking part in this study; Kerra Pearce and Mark Kristiansen (UCL Genomics) for processing the Illumina Infinium HumanMethylation450 BeadChips; Rasmus Bennet for technical assistance; and Laura Phipps for proofreading the manuscript. The BMBF Pediatric Diabetes Biobank recruits patients from the National Diabetes Patient Documentation System (DPV), and is financed by the German Ministry of Education and Research within the German Competence Net Diabetes Mellitus (01GI1106 and 01GI1109B). It was integrated into the German Center for Diabetes Research in January 2015. We thank the Swedish Research Council and SUS Funds for support. We gratefully acknowledge the participation of all NIHR Cambridge BioResource volunteers, and thank the Cambridge BioResource staff for their help with volunteer recruitment. We thank members of the Cambridge BioResource SAB and Management Committee for their support of our study and the NIHR Cambridge Biomedical Research Centre for funding. The Cardiovascular Epidemiology Unit is supported by the UK Medical Research Council (G0800270), BHF (SP/09/002), and NIHR Cambridge Biomedical Research Centre. Research in the Ouwehand laboratory is supported by the NIHR, BHF (PG-0310-1002 and RG/09/12/28096) and NHS Blood and Transplant. K.D. is funded as a HSST trainee by NHS Health Education England. M.F. is supported by the BHF Cambridge Centre of Excellence (RE/13/6/30180). A.D., E.L., L.C. and P.F. receive additional support from the European Molecular Biology Laboratory. A.K.S. is supported by an ADA Career Development Award (1-14-CD-17). B.O.B. and R.D.L. acknowledge support from the Deutsche Forschungsgemeinschaft (DFG) and European Federation for the Study of Diabetes, respectively

Validation of the Decipher Genomic Classifier in Patients receiving Salvage Radiotherapy without Hormone Therapy after Radical Prostatectomy - An Ancillary Study of the SAKK 09/10 Randomized Clinical Trial.

BACKGROUND The Decipher genomic classifier (GC) has shown to independently prognosticate outcomes in prostate cancer. The objective of this study was to validate the GC in a randomized phase 3 trial of dose-escalated salvage radiotherapy (SRT) after radical prostatectomy. PATIENTS AND METHODS A clinical grade whole-transcriptome assay was performed on RP samples obtained from patients enrolled in SAKK 09/10, a phase 3 trial of 350 men with biochemical recurrence post-radical prostatectomy randomized to 64Gy vs. 70Gy without concurrent hormonal therapy or pelvic nodal radiotherapy (RT). A pre-specified statistical plan was developed to assess the impact of the GC on clinical outcomes. The primary endpoint was biochemical progression; secondary endpoints were clinical progression and time to hormone therapy. Multivariable analyses adjusted for age, T-category, Gleason score, post-radical prostatectomy persistent prostate-specific antigen (PSA), PSA at randomization, and randomization arm were conducted, accounting for competing risks. RESULTS The analytic cohort of 226 patients was representative of the overall trial, with median follow-up of 6.3 years (IQR 6.1-7.2). GC (high vs. low-intermediate) was independently associated with biochemical progression (subdistribution hazard ratio [sHR] 2.26 [95% CI 1.42-3.60], p<0.001), clinical progression (HR 2.29 [95% CI 1.32-3.98], p=0.003), and use of hormone therapy (sHR 2.99 [95% CI 1.55-5.76], p=0.001). GC high patients had 5-year freedom from biochemical progression of 45% vs. 71% for GC low-intermediate. Dose escalation did not benefit the overall cohort, nor patients with lower vs. higher GC scores. CONCLUSIONS This study represents the first contemporary randomized controlled trial in patients treated with early SRT without concurrent hormone therapy or pelvic nodal RT that has validated the prognostic utility of the GC. Independent of standard clinicopathologic variables and RT dose, high-GC patients were more than twice as likely than lower-GC patients to experience biochemical and clinical progression and receive of salvage hormone therapy. This data confirms the clinical value of Decipher GC to personalize the use of concurrent systemic therapy in the postoperative salvage setting

Reconstructing cell cycle and disease progression using deep learning

We show that deep convolutional neural networks combined with nonlinear dimension reduction enable reconstructing biological processes based on raw image data. We demonstrate this by reconstructing the cell cycle of Jurkat cells and disease progression in diabetic retinopathy. In further analysis of Jurkat cells, we detect and separate a subpopulation of dead cells in an unsupervised manner and, in classifying discrete cell cycle stages, we reach a sixfold reduction in error rate compared to a recent approach based on boosting on image features. In contrast to previous methods, deep learning based predictions are fast enough for on-the-fly analysis in an imaging flow cytometer

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism