Publications by authors named "Anders Nielsen"

201 Publications

[Acute appendicitis after colonoscopy].

Ugeskr Laeger 2020 Dec;182(52)

Severe complications following colonoscopy are rare. This is a case report of a 44-year-old woman, who presented to an emergency department (ED) 24 hours following an uncomplicated colonoscopy performed in an out-patient clinic. Acute contrast-enhanced CT (CECT) was performed, showing acute appendicitis, which was later confirmed by a laparoscopy and histology. Weeks prior, the patient had been admitted to the ED with lower abdominal pain. On this occasion, CECT was performed, showing acute inflammation of the sigmoid colon.
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December 2020

Epithelial-to-mesenchymal transition is a resistance mechanism to sequential MET-TKI treatment of -amplified EGFR-TKI resistant non-small cell lung cancer cells.

Transl Lung Cancer Res 2020 Oct;9(5):1904-1914

Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Background: Tyrosine kinase inhibitor (TKI) resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC). amplification drives resistance to EGFR-TKIs in 5-20% of initially sensitive.

Egfr: mutated NSCLC patients, and combined treatment with EGFR-TKIs and MET-TKIs can overcome this resistance. Yet, inevitably MET-TKI resistance will also occur. Hence, knowledge on development of this sequential resistance is important for identifying the proper next step in treatment.

Methods: To investigate sequential resistance to MET-TKI treatment, we established a two-step TKI resistance model in -mutated HCC827 cells with amplification-mediated erlotinib resistance. These cells were subsequently treated with increasing doses of the MET-TKIs capmatinib or crizotinib in combination with erlotinib to establish resistance.

Results: In all the MET-TKI resistant cell lines, we systematically observed epithelial-to-mesenchymal transition (EMT) evident by decreased expression of E-cadherin and increased expression of vimentin and ZEB1. Furthermore, FGFR1 expression was increased in all MET-TKI resistant cell lines and four out of the six resistant cell lines had increased sensitivity to FGFR inhibition, indicating FGFR1-mediated bypass signaling.

Conclusions: EMT is common in the development of sequential EGFR-TKI and MET-TKI resistance in NSCLC cells. Our findings contribute to the evidence of EMT as a common TKI resistance mechanism.
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http://dx.doi.org/10.21037/tlcr-20-522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653150PMC
October 2020

Patient-reported outcomes in postmenopausal breast cancer survivors - comparisons with normative data.

Acta Oncol 2021 Jan 4;60(1):78-86. Epub 2020 Nov 4.

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.

Background: Survival rates for breast cancer (BC) are increasing, leading to growing interest in treatment-related late-effects. The aim of the present study was to explore late effects using Patient-Reported Outcome Measures in postmenopausal BC survivors in standard follow-up care. The results were compared to age- and gender-matched data from the general Danish population.

Material And Methods: Postmenopausal BC survivors in routine follow-up care between April 2016 and February 2018 at the Department of Oncology, Aarhus University Hospital, Denmark were asked to complete the EORTC QLQ-C30 and BR23 questionnaires together with three items on neuropathy, myalgia, and arthralgia from the PRO-CTCAE. Patients were at different time intervals from primary treatment, enabling a cross-sectional study of reported late effects at different time points after primary treatment. The time intervals used in the analysis were year ≤1, 1-2, 2-3, 3-4, 4-5 and 5+. The QLQ-C30 results were compared with reference data from the general Danish female population. Between-group differences are presented as effect sizes (ESs) (Cohen's ).

Results: A total of 1089 BC survivors participated. Compared with the reference group, BC survivors reported better global health status 2-3 and 4-5 years after surgery ( = 0.26) and physical functioning 2-3 years after (0.21). Poorer outcomes in BC survivors compared with the reference group were found for cognitive functioning (0-4 and 5+ years), fatigue (0-2 years), insomnia (1-3 years), emotional functioning (3-4 years), and social functioning (≤1 year after surgery) with ESs ranging from 0.20 to 0.41. For the remaining outcomes, no ESs exceeded 0.20.

Conclusion: Only small to medium ESs were found for better global health and physical functioning and poorer outcomes for cognitive functioning, fatigue, insomnia, emotional functioning, and social functioning in postmenopausal BC survivors, who otherwise reported similar overall health-related quality of life compared with the general Danish female population.
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http://dx.doi.org/10.1080/0284186X.2020.1834143DOI Listing
January 2021

Physiological condition of Eastern Baltic cod, , infected with the parasitic nematode .

Conserv Physiol 2020 22;8(1):coaa093. Epub 2020 Sep 22.

National Institute of Aquatic Resources, Technical University of Denmark (DTU Aqua), Kemitorvet 201, Kgs. Lyngby 2800, Denmark.

Establishing relationships between parasite infection and physiological condition of the host can be difficult and therefore are often neglected when describing factors causing population declines. Using the parasite-host system between the parasitic nematode and the Eastern Baltic cod , we here shed new light on how parasite load may relate to the physiological condition of a transport host. The Eastern Baltic cod is in distress, with declining nutritional conditions, disappearance of the larger fish, high natural mortality and no signs of recovery of the population. During the latest decade, high infection levels with have been observed in fish in the central and southern parts of the Baltic Sea. We investigated the aerobic performance, nutritional condition, organ masses, and plasma and proximate body composition of wild naturally infected in relation to infection density with . Fish with high infection densities of had (i) decreased nutritional condition, (ii) depressed energy turnover as evidenced by reduced standard metabolic rate, (iii) reduction in the digestive organ masses, and alongside (iv) changes in the plasma, body and liver composition, and fish energy source. The significantly reduced albumin to globulin ratio in highly infected suggests that the fish suffer from a chronic liver disease. Furthermore, fish with high infection loads had the lowest Fulton's condition factor. Yet, it remains unknown whether our results steam from a direct effect of , or because in an already compromised nutritional state are more susceptible towards the parasite. Nevertheless, impairment of the physiological condition can lead to reduced swimming performance, compromising foraging success while augmenting the risk of predation, potentially leading to an increase in the natural mortality of the host. We hence argue that fish-parasite interactions must not be neglected when implementing and refining strategies to rebuild deteriorating populations.
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http://dx.doi.org/10.1093/conphys/coaa093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507771PMC
September 2020

Cell-free Chromatin Immunoprecipitation (cfChIP) from blood plasma can determine gene-expression in tumors from non-small-cell lung cancer patients.

Lung Cancer 2020 09 23;147:244-251. Epub 2020 Jul 23.

Department of Biomedicine, Aarhus University, Denmark. Electronic address:

Objectives: Lung cancer is the leading cause of cancer related death worldwide. Accurate molecular diagnostics from a tumor biopsy is paramount for correct diagnosis, treatment strategy, and prediction of outcome. However, a tumor biopsy can be misleading due to tumor heterogeneity and consecutive biopsies are rarely achievable. Importantly, tumor-specific genetic information concerning mutations and translocations, can also be obtained from liquid biopsies, e.g. blood plasma, containing cell-free DNA (cfDNA) with both systemic and tumor origin. Tumor-specific gene-expression information can also be determined from liquid biopsies using cfDNA methylation and cell-free RNA analyses. However, supplementary methodologies that can determine gene-expression patterns in lung tumors from liquid biopsies could also have diagnostic impact.

Materials And Methods: We here present the method cell-free chromatin Immunoprecipitation (cfChIP), which for genes having high expression specifically in the tumor, can determine such gene-expression from blood plasma. In cfChIP cell-free nucleosomes modified with histone H3 lysine 36 tri-methylation (H3K36me3), a mark quantitatively correlated with the transcription of the underlying gene, are isolated, and associated cfDNA quantified.

Results: We demonstrate that cfChIP from lung cancer patient blood plasma can successfully quantify the level of H3K36me3 associated with circulating cell-free nucleosomes and thereby quantify the transcriptional level of genes associated with these nucleosomes. Moreover, as a proof-of-principle we show that in blood plasma from 14 lung cancer patients, H3K36me3 cfChIP can replicate the expected higher expression of KRT6 in lung squamous cell carcinoma relative to adenocarcinoma.

Conclusion: This work shows that for genes with a high expression specifically in tumor, cfChIP can determine this gene-expression pattern from blood plasma. cfChIP is a method that determine gene-expression at the transcriptional level and accordingly can supplement cfDNA methylation and cell-free RNA analyses.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.023DOI Listing
September 2020

Quantifying the effects of climate change on hydrological regime and stream biota in a groundwater-dominated catchment: A modelling approach combining SWAT-MODFLOW with flow-biota empirical models.

Sci Total Environ 2020 Nov 17;745:140933. Epub 2020 Jul 17.

Department of Bioscience, Aarhus University, Silkeborg, Denmark; Sino-Danish Centre for Education and Research, Beijing, China.

Climate change may affect stream ecosystems through flow regime alterations, which can be particularly complex in streams with a significant groundwater contribution. To quantify the impacts of climate change on hydrological regime and subsequently the stream biota, we linked SWAT-MODFLOW (A model coupling the Soil and Water Assessment Tool and the Modular Finite-difference Flow Model) with flow-biota empirical models that included indices for three key biological taxonomic identities (fish, macroinvertebrates and macrophytes) and applied the model-complex to a groundwater-dominated catchment in Denmark. Effects of predicted climate change towards the end of this century relative to the reference period (1996-2005) were tested with two contrasting climate change scenarios of different greenhouse gas emissions (Representative Concentration Pathway 2.6 (RCP 2.6) and RCP 8.5) and analysed for all subbasins grouped into streams of three size classes. The total water yield in the catchment did not change significantly (-1 ± 4 (SD) mm yr) from the baseline in the RCP2.6 scenario, while it increased by 9 ± 11 mm yr in the RCP8.5 scenario. The three stream size classes underwent different alterations in flow regime and also demonstrated different biotic responses to climate change. All large and some small streams were impacted most heavily by the climate change, where fish and macrophyte indices decreased up to 14.4% and 11.2%, respectively, whereas these indices increased by up to 14.4% and 6.0%, respectively, in the medium and some small streams. The climate change effects were, as expected, larger in the RCP8.5 scenario than in the RCP2.6 scenario. Our study is the first to quantify the impacts of streamflow alterations induced by climate change on stream biota beyond specific species.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140933DOI Listing
November 2020

Characterisation of recombinant factor IX before and after GlycoPEGylation.

Int J Pharm 2020 Oct 18;588:119654. Epub 2020 Jul 18.

Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Maaloev, Denmark.

The effect of the GlycoPEGylation process used for prolonging the half-life of recombinant factor IX (rFIX) has no impact on the primary and higher order structure of activated factor IX. Characterisation work performed on recombinant factor IX and on the GlycoPEGylated form of rFIX (N9-GP), confirm that the primary structure as well as the post translational modifications (PTMs) (disulphide bonds, γ-carboxylation, β-hydroxylation, sulphation and O- and N-linked glycan structures) were comparable for rFIX and N9-GP. Three O-linked glycan sites were identified in the activation peptide (Thr159, Thr163 and Thr169), where Thr163 has not been reported previously. For N9-GP, the mono GlycoPEGylation is directed toward one of the two N-linked glycans present at Asn157 and Asn167 in the activation peptide in a one to one ratio. Spectroscopic techniques, such as far and near UV Circular Dichroism studies show comparable secondary and tertiary structures of rFIX and N9-GP. The thermally induced unfolding of rFIX and N9-GP shows that the unfolding temperature is approximately 1 °C higher for N9-GP than that of the rFIX. Furthermore, the pH dependent degradation was reduced due to the GlycoPEGylation of rFIX. GlycoPEGylated rFIX (N9-GP) is used for the manufacturing of Refixia® (nonacog beta pegol, Rebinyn®, Novo Nordisk A/S, Bagsvaerd, Denmark).
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http://dx.doi.org/10.1016/j.ijpharm.2020.119654DOI Listing
October 2020

Enhancing pollination is more effective than increased conventional agriculture inputs for improving watermelon yields.

Ecol Evol 2020 Jun 23;10(12):5343-5353. Epub 2020 Apr 23.

Department of Landscape and Biodiversity Norwegian Institute of Bioeconomy Research (NIBIO) Ås Norway.

Agricultural practices to improve yields in small-scale farms in Africa usually focus on improving growing conditions for the crops by applying fertilizers, irrigation, and/or pesticides. This may, however, have limited effect on yield if the availability of effective pollinators is too low. In this study, we established an experiment to test whether soil fertility, soil moisture, and/or pollination was limiting watermelon () yields in Northern Tanzania. We subjected the experimental field to common farming practices while we treated selected plants with extrafertilizer applications, increased irrigation and/or extra pollination in a three-way factorial experiment. One week before harvest, we assessed yield from each plant, quantified as the number of mature fruits and their weights. We also assessed fruit shape since this may affect the market price. For the first fruit ripening on each plant, we also assessed sugar content (brix) and flesh color as measures of fruit quality for human consumption. Extra pollination significantly increased the probability of a plant producing a second fruit of a size the farmer could sell at the market, and also the fruit sugar content, whereas additional fertilizer applications or increased irrigation did not improve yields. In addition, we did not find significant effects of increased fertilizer or watering on fruit sugar, weight, or color. We concluded that, insufficient pollination is limiting watermelon yields in our experiment and we suggest that this may be a common situation in sub-Saharan Africa. It is therefore critically important that small-scale farmers understand the role of pollinators and understand their importance for agricultural production. Agricultural policies to improve yields in developing countries should therefore also include measures to improve pollination services by giving education and advisory services to farmers on how to develop pollinator-friendly habitats in agricultural landscapes.
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http://dx.doi.org/10.1002/ece3.6278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319119PMC
June 2020

Severe steroid refractory gastritis induced by Nivolumab: A case report.

World J Gastroenterol 2020 Apr;26(16):1971-1978

Department of Oncology, Aarhus University Hospital, Aarhus 8200, Denmark.

Background: Immune checkpoint inhibitors are widely used for treatment of many advanced malignancies. Lower gastrointestinal (GI) side effects, such as diarrhea and colitis, are common, but upper GI side effects are rarely reported. Consequently, the correct treatment of upper GI adverse events has been less frequently described.

Case Summary: We describe a case of a 16-year-old woman with stage IIIb malignant melanoma treated with adjuvant monotherapy using Nivolumab. The patient developed severe gastritis after six series of Nivolumab with weight loss, nausea, and vomiting. There was no effect of intravenous steroids, but the patient´s condition resolved after administration of Infliximab.

Conclusion: This case report supports the same treatment for gastritis as for colitis, which is in line with current guidelines.
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http://dx.doi.org/10.3748/wjg.v26.i16.1971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201147PMC
April 2020

Predicting ecosystem state changes in shallow lakes using an aquatic ecosystem model: Lake Hinge, Denmark, an example.

Ecol Appl 2020 10 11;30(7):e02160. Epub 2020 Jun 11.

Department of Bioscience, Aarhus University, 8600, Silkeborg, Denmark.

In recent years, considerable efforts have been made to restore turbid, phytoplankton-dominated shallow lakes to a clear-water state with high coverage of submerged macrophytes. Various dynamic lake models with simplified physical representations of vertical gradients, such as PCLake, have been used to predict external nutrient load thresholds for such nonlinear regime shifts. However, recent observational studies have questioned the concept of regime shifts by emphasizing that gradual changes are more common than sudden shifts. We investigated if regime shifts would be more gradual if the models account for depth-dependent heterogeneity of the system by including the possibility of vertical gradients in the water column and sediment layers for the entire depth. Hence, bifurcation analysis was undertaken using the 1D hydrodynamic model GOTM, accounting for vertical gradients, coupled to the aquatic ecosystem model PCLake, which is implemented in the framework for aquatic biogeochemical modeling (FABM). First, the model was calibrated and validated against a comprehensive data set covering two consecutive 7-yr periods from Lake Hinge, a shallow, eutrophic Danish lake. The autocalibration program Auto-Calibration Python (ACPy) was applied to achieve a more comprehensive adjustment of model parameters. The model simulations showed excellent agreement with observed data for water temperature, total nitrogen, and nitrate and good agreement for ammonium, total phosphorus, phosphate, and chlorophyll a concentrations. Zooplankton and macrophyte coverage were adequately simulated for the purpose of this study, and in general the GOTM-FABM-PCLake model simulations performed well compared with other model studies. In contrast to previous model studies ignoring depth heterogeneity, our bifurcation analysis revealed that the spatial extent and depth limitation of macrophytes as well as phytoplankton chlorophyll-a responded more gradually over time to a reduction in the external phosphorus load, albeit some hysteresis effects still appeared. In a management perspective, our study emphasizes the need to include depth heterogeneity in the model structure to more correctly determine at which external nutrient load a given lake changes ecosystem state to a clear-water condition.
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http://dx.doi.org/10.1002/eap.2160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583379PMC
October 2020

Identification of Binding Sites on Human Serum Albumin for Somapacitan, a Long-Acting Growth Hormone Derivative.

Biochemistry 2020 04 30;59(14):1410-1419. Epub 2020 Mar 30.

Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Måløv, Denmark.

Somapacitan, a human growth hormone derivative that binds reversibly to albumin, was investigated for human serum albumin (HSA) and HSA domain binding. Isothermal titration calorimetry (ITC) binding profiles showed high-affinity binding (∼100-1000 nM) of one somapacitan molecule and low-affinity binding (∼1000-10000 nM) of one to two somapacitan molecules to HSA. The high-affinity site was identified in HSA domain III using size exclusion chromatography (SEC) and ITC. SEC studies showed that the neonatal Fc receptor shields one binding site for somapacitan, indicating its position in domain III. A crystal structure of somapacitan in complex with HSA optimized for neonatal Fc receptor binding, having four amino acid residue replacements, identified a low-affinity site in fatty acid-binding site 6 (domain II). Surface plasmon resonance (SPR) showed these replacements affect the kinetics of the high-affinity binding site. Furthermore, small-angle X-ray scattering and SPR brace two somapacitan-binding sites on HSA.
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http://dx.doi.org/10.1021/acs.biochem.0c00019DOI Listing
April 2020

Assessing the impacts of groundwater abstractions on flow regime and stream biota: Combining SWAT-MODFLOW with flow-biota empirical models.

Sci Total Environ 2020 Mar 23;706:135702. Epub 2019 Nov 23.

Department of Bioscience, Aarhus University, Silkeborg, Denmark.

Assessing the impacts of groundwater abstractions on stream ecosystems is crucial for developing water planning and regulations in lowland areas that are highly dependent on groundwater, such as Denmark. To assess the effects of groundwater abstractions on flow regime and stream biota in a lowland groundwater-dominant catchment, we combined the SWAT-MODFLOW model with flow-biota empirical models including indices for three key biological taxonomic identities (fish, macroinvertebrates, and macrophytes). We assessed the effects of the current level of abstractions and also ran a scenario for assessing the effect of extreme groundwater abstractions (pumping rates of the drinking water wells were increased by 20 times in one subbasin of the catchment). Three subbasin outlets representing stream segments of different sizes were used for this evaluation. Current groundwater abstraction level had only minor impacts on the flow regime and stream biotic indices at the three subbasin outlets. The extreme abstractions, however, led to significant impacts on the small stream but had comparatively minor effects on the larger streams. The fish index responded most negatively to the groundwater abstractions, followed by the macrophyte index, decreasing, respectively, by 23.5% and 11.2% in the small stream in the extreme groundwater abstraction scenario. No apparent impact was found on macroinvertebrates in any of the three subbasin outlets. We conclude that this novel approach of a combined modelling system is a useful tool to quantitatively assess the effects of groundwater abstractions on stream biota and thereby support water planning and regulations related to groundwater abstractions. We highlight the need for developing improved biotic models that target specifically small headwater streams, which are often most affected by water abstraction.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135702DOI Listing
March 2020

The Gene Is a Noncanonical Interferon Gene with a Unique but Evolutionarily Conserved Regulation.

J Virol 2020 02 14;94(5). Epub 2020 Feb 14.

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

Interferon lambda 4 (IFN-λ4) is a recently identified enigmatic member of the interferon (IFN) lambda family. Genetic data suggest that the gene acts in a proviral and anti-inflammatory manner in patients. However, the protein is indistinguishable from the other members of the interferon lambda family. We have investigated the gene regulation of in detail and found that it differs radically from that of canonical antiviral interferons. Being induced by viral infection is a defining characteristic of interferons, but viral infection or overexpression of members of the interferon regulatory factor (IRF) family of transcription factors only leads to a minute induction of This behavior is evolutionarily conserved and can be reversed by inserting a functional IRF3 binding site into the promoter. Thus, the regulation of the gene is radically different and might explain some of the atypical phenotypes associated with the gene in humans. Recent genetic evidence has highlighted how the gene acts in a counterintuitive manner, as patients with a nonfunctional gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. This suggests that the gene acts in a proviral and anti-inflammatory manner. These surprising but quite clear genetic data have prompted an extensive examination of the basic characteristics of the gene and its gene product, interferon lambda 4 (IFN-λ4). We have investigated the expression of the gene and found it to be poorly induced by viral infections. A thorough investigation of the promoter revealed a highly conserved and functional promoter, but also one that lacks the defining characteristic of interferons (IFNs), i.e., the ability to be effectively induced by viral infections. We suggest that the unique function of the gene is related to its noncanonical transcriptional regulation.
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http://dx.doi.org/10.1128/JVI.01535-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022339PMC
February 2020

Single-spin vector analysis of strongly coupled nuclei in TOCSY NMR experiments.

J Chem Phys 2019 Oct;151(13):134117

Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, DK-8000 Aarhus C, Denmark.

This paper presents a new way to represent the effect of complex radio-frequency (rf) pulse sequences on J-coupled nuclear spin systems. The model uses a vector representation of the single-spin interactions (chemical-shift and rf interactions) and provides a simple route to gain analytical insight into multipulse NMR experiments. The single-spin Hamiltonian is expressed in an interaction representation as Fourier components. These Fourier components are combined for the two spins to establish the averaged coupling term of the Hamiltonian. This effective Hamiltonian is fast to calculate as only single-spin rotations are used and followed by simple summation of numbers for reconstruction of given coupling interactions. The present method is used to gain analytical insight into the performance of the J-coupling transfer sequence DIPSI-2 through two figures of merit (FOM) providing useful information for optimization of such pulse sequences. The first FOM (Ξ) reports the efficiency of the desired total correlation spectroscopy transfer and should be as large as possible, while the second (Ξ) reports the potential leakage of coherence to a heteronuclear spin and should be as small as possible.
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http://dx.doi.org/10.1063/1.5123046DOI Listing
October 2019

PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer.

Cancer Commun (Lond) 2019 06 3;39(1):30. Epub 2019 Jun 3.

Department of Biomedicine, Aarhus University, 8000, Aarhus C, Denmark.

Background: Programmed cell death ligand-1 (PD-L1) and ligand-2 (PD-L2) interaction with programmed cell death protein-1 (PD-1) represent an immune-inhibiting checkpoint mediating immune evasion and is, accordingly, an important target for blockade-based immunotherapy in cancer. In non-small-cell lung cancer (NSCLC), improved understanding of PD-1 checkpoint blockade-responsive biology and identification of biomarkers for prediction of a clinical response to immunotherapy is warranted. Thus, in the present study, we systematically described PD-L1 and PD-L2 expression correlated genes in NSCLC.

Methods: We performed comparative retrospective analyses to identify PD-L1 and PD-L2 mRNA expression correlated genes in NSCLC. For this, we examined available datasets from the cancer cell line encyclopedia (CCLE) project lung non-small-cell (Lung_NSC) and the cancer genome atlas (TCGA) projects lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).

Results: Analysis of the CCLE dataset Lung_NSC identified expression correlation between PD-L1 and PD-L2. Moreover, we identified expression correlation between 489 genes and PD-L1, 191 genes and PD-L2, and 111 genes for both. PD-L1 and PD-L2 also expression correlated in TCGA datasets LUAD and LUSC. In LUAD, we identified expression correlation between 257 genes and PD-L1, 914 genes and PD-L2, and 211 genes for both. In LUSC, we identified expression correlation between 26 genes and PD-L1, 326 genes and PD-L2, and 13 genes for both. Only a few genes expression correlated with PD-L1 and PD-L2 across the CCLE and TCGA datasets. Expression of Interferon signaling-involved genes converged in particular with the expression correlated genes for PD-L1 in Lung_NSC, for PD-L2 in LUSC, and for both PD-L1 and PD-L2 in LUAD. In LUSC, PD-L1, and to a lesser extent PD-L2, expression correlated with chromosome 9p24 localized genes, indicating a chromosome 9p24 topologically associated domain as an important driver of in particular LUSC PD-L1 expression. Expression correlation analyses of the PD-L1 and PD-L2 receptors programmed cell death protein-1 (PD-1), Cluster of differentiation 80 (CD80), and Repulsive guidance molecule B (RGMB) showed that PD-1 and CD80 expression correlated with both PD-L1 and PD-L2 in LUAD. CD80 expression correlated with PD-L2 in LUSC.

Conclusions: We present gene signatures associated with PD-L1 and PD-L2 mRNA expression in NSCLC which could possess importance in relation to understand PD-1 checkpoint blockade-responsive biology and development of gene signature based biomarkers for predicting clinical responses to immunotherapy.
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http://dx.doi.org/10.1186/s40880-019-0376-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545701PMC
June 2019

Cause-and-Effect relationship between FGFR1 expression and epithelial-mesenchymal transition in EGFR-mutated non-small cell lung cancer cells.

Lung Cancer 2019 06 18;132:132-140. Epub 2019 Apr 18.

Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address:

Objectives: Increased FGFR1 expression is associated with resistance to tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC cells and often concomitant with epithelial to mesenchymal transition (EMT). However, the cause-and-effect relationship between increased FGFR1 expression and EMT in the genetic background of EGFR-mutated non-small cell lung cancer (NSCLC) cells is not clear. Previous studies have specifically addressed the relationship between EMT and increased FGFR1 expression in the context of simultaneous TKI-mediated blocking of EGFR-signaling. Here, in the context of EGFR-mutated NSCLC cells with active EGFR-signaling, we have examined whether increased FGFR1 expression drives EMT or is an EMT passenger event.

Materials And Methods: For cause-and-effect analyses between EMT and FGFR1 expression, including expression of alternative spliced FGFR1 isoforms, we used CRISPR-dCAS9-SAM-mediated induction of the endogenous FGFR1 and ZEB1 genes, as well as biochemical EMT-induction, in PC9 and HCC827 NSCLC cell lines harboring activating EGFR-mutations.

Results: We find that FGFR1 expression correlates with a ZEB1-associated EMT gene expression profile in NSCLC cells. In experiments using NSCLC cell lines harboring activating EGFR-mutations we show that CRISPR-dCAS9-SAM-mediated induction of FGFR1 expression is neither driving an increase in ZEB1 expression nor EMT characteristics. However, CRISPR-dCAS9-SAM-mediated induction of ZEB1 expression drives EMT characteristics and an increase in FGFR1 expression. Biochemical induction of EMT also drives an increase in FGFR1 expression.

Conclusion: From our findings concerning the cause-and-effect relationship in the genetic background of EGFR-mutated NSCLC cells, we conclude that an increase in ZEB1 expression is a driver of EMT resulting in concomitant increased FGFR1 expression, whereas an increase in FGFR1 expression is insufficient to drive concomitant EMT.
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http://dx.doi.org/10.1016/j.lungcan.2019.04.023DOI Listing
June 2019

Fluorescent Pan Traps Affect the Capture Rate of Insect Orders in Different Ways.

Insects 2019 Feb 1;10(2). Epub 2019 Feb 1.

School of Media and Communication, RMIT University, Melbourne, VIC 3001, Australia.

To monitor and quantify the changes in pollinator communities over time, it is important to have robust survey techniques of insect populations. Pan traps allow for the assessment of the relative insect abundance in an environment and have been promoted by the Food and Agricultural Organization (FAO) as an efficient data collection methodology. It has been proposed that fluorescent pan traps are particularly useful, as it has been suggested that they capture high numbers of insects in an unbiased fashion. We use a simultaneous presentation of fluorescent and non-fluorescent pan trap colours to assess how flower-visiting insects of different orders respond to visual stimuli and reveal a significant interaction between trap fluorescence and captured insect type. In particular, Coleoptera (beetles) and Lepidoptera (butterflies and moths) were captured significantly more frequently by fluorescent traps, whilst Dipterans (flies) were captured significantly less frequently by this type of pan trap. Hymenopterans (bees and wasps) showed no significant difference in their preference for fluorescent or non-fluorescent traps. Our results reveal that the use of fluorescent pan traps may differently bias insect capture rates when compared to the typical experience of colour flower-visiting insects in natural environments. Correction factors may, therefore, be required for interpreting insect pan trap data collected with different methodologies.
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http://dx.doi.org/10.3390/insects10020040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410105PMC
February 2019

Effects of changes in land use and climate on aquatic ecosystems: Coupling of models and decomposition of uncertainties.

Sci Total Environ 2019 Mar 5;657:627-633. Epub 2018 Dec 5.

Aarhus University, Department of Bioscience, Silkeborg, Denmark; Sino-Danish Center for Education and Research (SDC), Aarhus, Denmark; Sino-Danish Center for Education and Research (SDC), Beijing, China.

To analyse the potential future ecological state of estuaries located in the temperate climate (here exemplified with the Odense Fjord estuary, Denmark), we combined end-of-the-century climate change projections from four different climate models, four contrasting land use scenarios ("Agriculture for nature", "Extensive agriculture", "High-tech agriculture" and "Market driven agriculture") and two different eco-hydrological models. By decomposing the variance of the model-simulated output from all scenario and model combinations, we identified the key sources of uncertainties of these future projections. There was generally a decline in the ecological state of the estuary in scenarios with a warmer climate. Strikingly, even the most nature-friendly land use scenario, where a proportion of the intensive agricultural area was converted to forest, may not be enough to counteract the negative effects of a future warmer climate on the ecological state of the estuary. The different land use scenarios were the most significant sources of uncertainty in the projections of future ecological state, followed, in order, by eco-hydrological models and climate models, albeit all three sources caused high variability in the simulated outputs. Therefore, when projecting the future state of aquatic ecosystems in a global warming context, one should at the very least consider to evaluate an ensemble of land use scenarios (nutrient loads) but ideally also include multiple eco-hydrological models and climate change projections. Our study may set precedence for future attempts to predict and quantify uncertainties of model and model input ensembles, as this will likely be key elements in future tools for decision-making processes.
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http://dx.doi.org/10.1016/j.scitotenv.2018.12.055DOI Listing
March 2019

Pyromellitic dianhydride (PMDA) may cause occupational asthma.

Occup Environ Med 2019 03 11;76(3):175-177. Epub 2019 Jan 11.

Department of Occupational and Environmental Medicine, Odense University Hospital, Odense, Denmark.

Introduction: Anhydrides are widely used as cross-linking agents in epoxy resins and alkyd production, for example, as coatings and adhesives in plastic products. Sensitisation to several anhydrides is known to cause occupational asthma. There are indications that the lesser known pyromellitic dianhydride (PMDA) can cause irritative respiratory symptoms and possibly asthma. We report three cases of workers from a plastic foil manufacturing plant, who developed asthma when exposed to PMDA during specific inhalation challenge (SIC).

Methods: SIC was performed over 2 days according to recommendations of European Respiratory Society. Lactose powder was used in control challenges and a mixture of 10% PMDA and 90% lactose powder in active challenges.

Results: All cases experienced a delayed decrease in forced expiratory flow in 1 s (FEV) 4-12 hours after active challenge. FEV decreased by 19%, 15% and 16%, respectively. After 21 hours, FEV decreased by 24% in one worker.

Discussion: Respiratory symptoms after working hours may represent delayed work-related asthma. During SIC, the three patients developed lower respiratory symptoms and a delayed decrease in FEV which suggest sensitisation. The mechanism of anhydride-related asthma is not well understood. Anhydrides are known irritants and hence an irritative response cannot be excluded. The company improved ventilation and enforced the use of respiratory protection equipment, and finally phased out PMDA. Occupational workplace risk identification may help to identify exposures. SIC can contribute to improving working conditions, by identifying and confirming asthmogens in the environment.
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http://dx.doi.org/10.1136/oemed-2018-105295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581108PMC
March 2019

Up-Regulated FGFR1 Expression as a Mediator of Intrinsic TKI Resistance in EGFR-Mutated NSCLC.

Transl Oncol 2019 Mar 16;12(3):432-440. Epub 2018 Dec 16.

Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address:

Non-small cell lung carcinoma patients with epidermal growth factor receptor (EGFR) mutations are offered EGFR tyrosine kinase inhibitors (TKI) as first line treatment, but 20-40% of these patients do not respond. High expression of alternative receptor tyrosine kinases, such as Fibroblast growth factor receptor 1 (FGFR1), potentially mediates intrinsic EGFR TKI resistance. To study this in molecular detail, we used CRISPR-dCas9 Synergistic Activation Mediator (SAM) for up-regulation of FGFR1 in physiological relevant levels in the EGFR mutated NSCLC cell lines HCC827 and PC9 thereby generating HCC827 and PC9. The sensitivity to the TKI erlotinib was investigated in vitro and in a BALBc nu/nu mouse xenograft model. FGFR1 up-regulation decreased TKI-sensitivity in both NSCLC cell lines in the presence of the ligand fibroblast growth factor 2 (FGF2). Xenografts were established with PC9 cells and it was demonstrated that there was no significant difference in tumor size between TKI- and vehicle-treated PC9 tumors. This supports decreased TKI-sensitivity in NSCLC cells with FGFR1 up-regulation. Our study points to FGFR1 signaling being an intrinsic resistance mechanism abolishing TKI response in EGFR mutated NSCLC.
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http://dx.doi.org/10.1016/j.tranon.2018.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297127PMC
March 2019

Using virtual-reality simulation to ensure basic competence in hysteroscopy.

Surg Endosc 2019 07 17;33(7):2162-2168. Epub 2018 Oct 17.

SimC, Odense University Hospital, Odense, Region of Southern Denmark, Denmark.

Background: Hysteroscopy is a technically challenging procedure. Specialty curricula of obstetrics and gynaecology appraise hysteroscopy for trainees but there is no present evidence-based training program that certifies the fundamental technical skills before performance on patients. The objectives of this study were to develop and gather validity evidence for a simulation-based test that can ensure basic competence in hysteroscopy.

Methods: We used the virtual-reality simulator HystMentor™. Six experts evaluated the feasibility and clinical relevance of the simulator modules. Six modules were selected for the test and a pilot study was carried out. Subsequently, medical students, residents, and experienced gynaecologists were enrolled for testing. Outcomes were based on generated simulator metrics. Validity evidence was explored for all five sources of evidence (content, response process, internal structure, relations to other variables, consequences of testing).

Results: Inter-case reliability was high for four out of five metrics (Cronbach's alpha ≥ 0.80). Significant differences were identified when comparing the three groups' performances (p values < 0.05). Participants' clinical experience was significantly correlated to their simulator test score (Pearson's r = 0.49, p < 0.001). A single medical student managed to achieve the established pass/fail score (6.7% false positive) and three experienced gynaecologists failed the test (27.3% false negative).

Conclusions: We developed a virtual-reality simulation-based test in hysteroscopy with supporting validity evidence. The test is intended to ensure competency in a mastery learning program where trainees practise on the simulator until they are able to pass before they proceed to supervised training on patients.
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http://dx.doi.org/10.1007/s00464-018-6495-3DOI Listing
July 2019

Benthic habitat selection in juvenile European eel Anguilla anguilla: implications for coastal habitat management and restoration.

J Fish Biol 2018 Nov;93(5):996-999

Section for Ecosystem based Marine Management, Technical University of Denmark, National Institute of Aquatic Resources (DTU Aqua), Lyngby, Denmark.

The critically endangered European eel Anguilla anguilla is dependent on suitable habitat qualities over a vast geographic area. Even though a significant proportion of the population never enters fresh water, the preferred benthic habitat is largely unknown in the marine environment. Examining substratum selection in A. anguilla reveals that elvers prefer coarse gravel, suggesting that conservation efforts may benefit from targeting this type of substratum in marine coastal areas.
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http://dx.doi.org/10.1111/jfb.13807DOI Listing
November 2018

The influence of paternal diet on sncRNA-mediated epigenetic inheritance.

Mol Genet Genomics 2019 Feb 18;294(1):1-11. Epub 2018 Sep 18.

Department of Biomedicine, Aarhus University, Bartholin Building, 8000, Aarhus C, Denmark.

The risk of developing metabolic diseases is conferred by genetic predisposition from risk genes and by environmental exposures that can manifest in epigenetic changes. The global rise in obesity and type II diabetes has motivated a search for the epigenetic factors underlying these diseases. The possibility of transgenerational inheritance of epigenetic changes raises questions regarding how spermatozoa transmit acquired epigenetic changes that affect the metabolic health of the next generation. The purpose of this review is to describe current key literature concerning small non-coding RNA (sncRNA), specifically (1) the effects of high-fat or low-protein diets on sncRNA presence in spermatozoa; (2) sncRNA transmission from father to offspring; and (3) the functional effects of inherited sncRNA on offspring metabolic phenotype. Current research has identified alterations in the content of sncRNA subtypes, including microRNA (miRNA), Piwi-interacting RNA (piRNA), and transferRNA (tRNA)-derived small non-coding RNA (tsncRNA), in spermatozoa in response to both high-fat diets and low-protein diets. The altered content of spermatozoa sncRNA due to high-fat diets was associated with a changed phenotype in offspring, with offspring displaying insulin resistance, altered body weight, and glucose intolerance. The altered sncRNA content of spermatozoa due to a low-protein diet was associated with altered levels of lipid metabolites in offspring and decreased expression of specific genes starting in two-cell embryos. The current literature suggests that sncRNAs mediate paternal intergenerational epigenetic inheritance and thus has a direct functional importance, as well as possess biomarker potential, for metabolic diseases. Further research is urgently required to identify the specific sncRNAs with the most profound impacts.
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http://dx.doi.org/10.1007/s00438-018-1492-8DOI Listing
February 2019

Growth and food consumption of whiting Merlangius merlangus.

J Fish Biol 2018 Aug;93(2):334-343

Technical University of Denmark, National Institute of Aquatic Resources, Kgs. Lyngby, Denmark.

In the western Baltic Sea (WBS), whiting Merlangius merlangus is the main piscivorous fish together with cod Gadus morhua. In the present study, we investigate the growth and food consumption rates of WBS M. merlangus and compare the growth rates of males and females with those of M. merlangus in the North Sea (NS). Food consumption rates are estimated directly from sampled stomach contents in the WBS using a gastric evacuation rate model and indirectly by using a static energy-budget model together with the growth rates. The results indicate that male and female M. merlangus in the WBS have similar feeding and growth strategies, while in the NS M. merlangus show more pronounced differences in food consumption and growth dynamics between the sexes. Female WBS M. merlangus grow significantly slower than their conspecifics in the NS, but there is no significant difference for males. Sexual size dimorphism is seen in both areas, but for M. merlangus in the WBS the difference is less pronounced. Food consumption rates in the WBS differ between seasons, with the lowest food intake in the first 2 quarters of the year and the highest in the 3rd quarter. No differences in consumption rates were seen between males and females, which could be related to the more similar growth pattern seen for M. merlangus in the WBS.
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http://dx.doi.org/10.1111/jfb.13763DOI Listing
August 2018

No one can whistle a symphony: how hospitals design for daily cross-boundary collaboration.

J Health Organ Manag 2018 Jun 7;32(4):618-634. Epub 2018 Jun 7.

Sustainable Production, Aalborg University Copenhagen , Copenhagen, Denmark.

Purpose The purpose of this paper is to investigate how and with which mechanisms health care professionals in practice design for collaboration to solve collective hospital tasks, which cross occupational and departmental boundaries. Design/methodology/approach An in-depth multiple-case study of five departments across four hospitals facing fast to slow response task requirements was carried out using interviews and observations. The selected cases were revealing as the departments had designed and formalized their daily hospital operations differently to solve collaboration and performance issues. Findings Local collaboration across occupational and departmental boundaries requires bundles of behavioral formalization elements (e.g. standardized plans, resource allocation decisions, assigned formal roles, and handoff routines), and liaison devices (e.g. huddles, boards, and physical proximity), which are used in parallel or sequence. The authors label this "designed collaboration bundles." These bundles supplement the central organizational structures, processes, and support systems less capable of ensuring fluent coordination at the front line. Practical implications Health care professionals and hospital managers can consider designing bundles of organizational design features to proactively develop and ensure collaboration capable of solving collective tasks and bridging departmental and occupational silos to improve health care delivery. Originality/value This research paper addresses the fundamental organizational challenge of how to achieve efficient collaboration by studying how formal structures and processes are used in combination on the hospital floor, thereby going beyond previous research that studies these mechanisms individually.
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http://dx.doi.org/10.1108/JHOM-10-2017-0265DOI Listing
June 2018

Bee conservation: Inclusive solutions.

Science 2018 04 26;360(6387):389-390. Epub 2018 Apr 26.

Helmholtz Centre for Environmental Research-UFZ, Department of Community Ecology, 06120 Halle, Germany.

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http://dx.doi.org/10.1126/science.aat2054DOI Listing
April 2018

Genome-wide determination of on-target and off-target characteristics for RNA-guided DNA methylation by dCas9 methyltransferases.

Gigascience 2018 03;7(3):1-19

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

Background: Fusion of DNA methyltransferase domains to the nuclease-deficient clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9 (dCas9) has been used for epigenome editing, but the specificities of these dCas9 methyltransferases have not been fully investigated.

Findings: We generated CRISPR-guided DNA methyltransferases by fusing the catalytic domain of DNMT3A or DNMT3B to the C terminus of the dCas9 protein from Streptococcus pyogenes and validated its on-target and global off-target characteristics. Using targeted quantitative bisulfite pyrosequencing, we prove that dCas9-BFP-DNMT3A and dCas9-BFP-DNMT3B can efficiently methylate the CpG dinucleotides flanking its target sites at different genomic loci (uPA and TGFBR3) in human embryonic kidney cells (HEK293T). Furthermore, we conducted whole genome bisulfite sequencing (WGBS) to address the specificity of our dCas9 methyltransferases. WGBS revealed that although dCas9-BFP-DNMT3A and dCas9-BFP-DNMT3B did not cause global methylation changes, a substantial number (more than 1000) of the off-target differentially methylated regions (DMRs) were identified. The off-target DMRs, which were hypermethylated in cells expressing dCas9 methyltransferase and guide RNAs, were predominantly found in promoter regions, 5΄ untranslated regions, CpG islands, and DNase I hypersensitivity sites, whereas unexpected hypomethylated off-target DMRs were significantly enriched in repeated sequences. Through chromatin immunoprecipitation with massive parallel DNA sequencing analysis, we further revealed that these off-target DMRs were weakly correlated with dCas9 off-target binding sites. Using quantitative polymerase chain reaction, RNA sequencing, and fluorescence reporter cells, we also found that dCas9-BFP-DNMT3A and dCas9-BFP-DNMT3B can mediate transient inhibition of gene expression, which might be caused by dCas9-mediated de novo DNA methylation as well as interference with transcription.

Conclusion: Our results prove that dCas9 methyltransferases cause efficient RNA-guided methylation of specific endogenous CpGs. However, there is significant off-target methylation indicating that further improvements of the specificity of CRISPR-dCas9 based DNA methylation modifiers are required.
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http://dx.doi.org/10.1093/gigascience/giy011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888497PMC
March 2018

Simple method for assembly of CRISPR synergistic activation mediator gRNA expression array.

J Biotechnol 2018 May 26;274:54-57. Epub 2018 Mar 26.

Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. Electronic address:

When studying complex interconnected regulatory networks, effective methods for simultaneously manipulating multiple genes expression are paramount. Previously, we have developed a simple method for generation of an all-in-one CRISPR gRNA expression array. We here present a Golden Gate Assembly-based system of synergistic activation mediator (SAM) compatible CRISPR/dCas9 gRNA expression array for the simultaneous activation of multiple genes. Using this system, we demonstrated the simultaneous activation of the transcription factors, TWIST, SNAIL, SLUG, and ZEB1 a human breast cancer cell line.
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http://dx.doi.org/10.1016/j.jbiotec.2018.03.018DOI Listing
May 2018

DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line.

J Mol Endocrinol 2018 02 4;60(2):R39-R56. Epub 2017 Dec 4.

Department of Biomedicine, Aarhus University, Aarhus, Denmark.

The global rise in metabolic diseases can be attributed to a complex interplay between biology, behavior and environmental factors. This article reviews the current literature concerning DNA methylation-based epigenetic inheritance (intergenerational and transgenerational) of metabolic diseases through the male germ line. Included are a presentation of the basic principles for DNA methylation in developmental programming, and a description of windows of susceptibility for the inheritance of environmentally induced aberrations in DNA methylation and their associated metabolic disease phenotypes. To this end, escapees, genomic regions with the intrinsic potential to transmit acquired paternal epigenetic information across generations by escaping the extensive programmed DNA demethylation that occurs during gametogenesis and in the zygote, are described. The ongoing descriptive and functional examinations of DNA methylation in the relevant biological samples, in conjugation with analyses of non-coding RNA and histone modifications, hold promise for improved delineation of the effect size and mechanistic background for epigenetic inheritance of metabolic diseases.
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http://dx.doi.org/10.1530/JME-17-0189DOI Listing
February 2018