Impact of Long‐Term Alcohol Consumption and Relapse on Genome‐Wide DNA Methylation Changes in Alcohol‐Dependent Subjects: A Longitudinal Study

Background: Genetic factors play an important role in the development and maintenance of alcohol use disorder (AUD). Significant and widespread differences in methylation levels of multiple regions within the genome have been reported between AUD patients and healthy controls in large epigenome-wide association studies (EWASs). Also, within patient populations, methylation changes over time (both during and after withdrawal) have been identified as sensitive indicators for disease activity. The detection of changes in methylation levels is a powerful tool to further explore and understand the biological correlates and underpinnings of AUD. Although there is strong and convincing evidence for differences in methylation of various sites between AUD patients and controls, only few studies assessed changes within patients over longer periods of time while taking into account alcohol consumption, relapse, and abstinence. So far, the longest period assessed as a within-subject design using EWASs was 4 weeks. Methods: Here, we investigated changes in whole-genome methylation levels within a sample of 69 detoxified AUD patients over a period as long as 12 months for the first time, comparing patients that relapsed within the follow-up period to those that remained abstinent. Results: Whole-genome methylation patterns of individual CpG sites over time did not differ between abstinent and relapsing patients. However, there was a negative association between global mean methylation at the 12-month follow-up and alcohol consumption within our sample. Conclusion: Although the present study represents the largest study of methylation levels in a sample of AUD patients with a follow-up period of 1 year and accounting for alcohol consumption and relapse to date, the sample size might still not be large enough to detect genome-wide significant effects. Therefore, large-scale, long-term studies with AUD subjects are needed to determine the utility of DNA methylation for the assessment and monitoring of persons with alcohol use disorders

Addendum to: Capillary floating and the billiard ball problem

We compare the results of our earlier paper on the floating in neutral equilibrium at arbitrary orientation in the sense of Finn-Young with the literature on its counterpart in the sense of Archimedes. We add a few remarks of personal and social-historical character.Comment: This is an addendum to my article Capillary floating and the billiard ball problem, Journal of Mathematical Fluid Mechanics 14 (2012), 363 -- 38

Practical robustness evaluation in radiotherapy - A photon and proton-proof alternative to PTV-based plan evaluation

Background and purpose: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-base

Petrogenesis of Eocene Tamazert continental carbonatites (Central High Atlas, Morocco): implications for a common source for the Tamazert and Canary and Cape Verde Island carbonatites

The Tamazert Eocene alkaline complex of the Central High Atlas Range of Morocco hosts the largest outcropping occurrences of carbonatites in northern Africa. The complex consists of carbonatites and undersaturated ultramafic to syenitic alkaline to peralkaline silicate rocks. Mineralogically and geochemically the Tamazert carbonatites are classified as calciocarbonatites, magnesiocarbonatites and silicocarbonatites.They are enriched in light rare earth elements and large ion lithophile elements (Cs, Rb, Ba, U,Th), but depleted in high field strength elements (particularly, Ti, Nb and Ta). Stable and radiogenic isotope ratios vary in the range of δ13CPDB=-5·8 to 1·8 0/00, δ18OSMOW=6·9-23·5 0/00, initial 87Sr/86Sr=0·7031-0·7076, 143Nd/144Nd=0·5125-0·5129 and 206Pb/204Pb=18·29-19·89. Calciocarbonatites intruding Jurassic limestones have the highest δ13C and δ18O values and the most radiogenic initial 87Sr/86Sr, but least radiogenic 143Nd/144Nd, 206Pb/204Pb and 208Pb/204Pb isotope ratios, and are interpreted to have interacted with the limestones (crustal components). The magnesio- and silicocarbonatites have Sr, Nd and Pb isotope ratios that are nearly identical to those of low-87Sr/86Sr calciocarbonatites. The isotope signature of the high-Sr, low-87Sr/86Sr calciocarbonatites with mantle-type O and C isotopic compositions indicates the presence of HIMU- and EMI-type components in the mantle source of the Tamazert carbonatites, similar to what has been proposed for the Cape Verde and Canary Islands.The close similarity in carbonatite composition between the Cape Verde and Canary Islands and Tamazert suggests a common sublithospheric source for these carbonatites. We therefore propose that theTamazert carbonatites originated through melting of Canary plume material that may have flowed through a sub-lithospheric corridor extending from the Atlantic near the Canary Islands to the Middle Atlas, formed by the delamination of the subcontinental lithosphere in response to Africa-Europe collision at c. 42Ma. Seismic tomography data suggest that the common source may be within the lower mantle at depths >1000 km

Practical robustness evaluation in radiotherapy - A photon and proton-proof alternative to PTV-based plan evaluation

Background and purpose: A planning target volume (PTV) in photon treatments aims to ensure that the clinical target volume (CTV) receives adequate dose despite treatment uncertainties. The underlying static dose cloud approximation (the assumption that the dose distribution is invariant to errors) is problematic in intensity modulated proton treatments where range errors should be taken into account as well. The purpose of this work is to introduce a robustness evaluation method that is applicable to photon and proton treatments and is consistent with (historic) PTV-based treatment plan evaluations. Materials and methods: The limitation of the static dose cloud approximation was solved in a multi-scenario simulation by explicitly calculating doses for various treatment scenarios that describe possible errors in the treatment course. Setup errors were the same as the CTV-PTV margin and the underlying theory of 3D probability density distributions was extended to 4D to include range errors, maintaining a 90% confidence level. Scenario dose distributions were reduced to voxel-wise minimum and maximum dose distributions; the first to evaluate CTV coverage and the second for hot spots. Acceptance criteria for CTV D98 and D2 were calibrated against PTV-based criteria from historic photon treatment plans. Results: CTV D98 in worst case scenario dose and voxel-wise minimum dose showed a very strong correlation with scenario average D98 (R-2 > 0.99). The voxel-wise minimum dose visualised CTV dose conformity and coverage in 3D in agreement with PTV-based evaluation in photon therapy. Criteria for CTV D98 and D2 of the voxel-wise minimum and maximum dose showed very strong correlations to PTV D98 and D2 (R-2 > 0.99) and on average needed corrections of -0.9% and +2.3%, respectively. Conclusions: A practical approach to robustness evaluation was provided and clinically implemented for PTV-less photon and proton treatment planning, consistent with PTV evaluations but without its static dose cloud approximation. (C) 2019 The Authors. Published by Elsevier B.V

Compositional characteristics and spatial distribution of enriched Icelandic mantle components

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Journal of Petrology 51 (2010): 1447-1475, doi:10.1093/petrology/egq025.We present compositional data on a suite of 18 primitive neovolcanic alkali basalts from three flank zone regions in Iceland (Vestmannaeyjar in the south, Snæfell in the east, and Snæfellsnes in the west) that are peripheral to the main rift zones that are dominated by tholeiitic basalts. This study integrates He isotope data with radiogenic isotope data (Sr-Nd-Pb-Hf), stable isotope data (δ18O), and trace element data to characterise the compositional features of the trace-elementenriched components of the Icelandic mantle. We also present high-precision Pb isotope data on an additional 57 lava samples from the flank zones (including Öræfajökull in the south-east) and the Northern and Eastern rift zones. Most Icelandic lavas have negative Δ207Pb (–4 to –1), with higher values (–1 to +4) found only in samples from Öræfajökull, Snæfell, and parts of the Reykjanes Peninsula. At Snæfell, this EM1-type component is characterised by a low δ18Oolivine signature (+4.1‰ to +4.6‰), moderate 206Pb/204Pb values (18.4-18.6) and MORB-like 3He/4He (6.9-7.5 R/RA). Samples from Vestmannaeyjar and Snæfellsnes have mantle-like δ18Oolivine (+4.9‰ to +5.0‰), and radiogenic 206Pb/204Pb values (18.9-19.3) that fall on the NHRL for 208Pb/204Pb (Δ208Pb –5 to +5). Compared to the Vestmannaeyjar lavas, Snæfellsnes lavas have higher La/YbN (5-11 vs. 3-5), lower εNd (5.5-6.5 vs. 6.8-7.6) and lower 3He/4He (6.3-8.6 R/RA vs. 11.4-13.5 R/RA). Therefore, the most trace element enriched components in the Icelandic mantle are not the carriers of the high 3He/4He values (> 15 R/RA) found in some lavas on Iceland and the adjacent ridges, and instead are consistent with degassed, recycled components. Even after excluding the EM1-type high Δ207Pb samples, high-precision Pb isotope data produce a kinked array on an 206Pb/204Pb vs. 208Pb/204Pb plot, which is not consistent with simple binary mixing between two end-members. This requires significant lateral heterogeneity within the Icelandic mantle and the presence of more than just two compositionally-distinct local mixing end-member components. Samples from each of the main axial rift zones define different trends. Despite the tectonic continuity between the Northern Volcanic Zone and the Eastern Volcanic Zone, lavas from these two rift zones define separate sub-parallel linear arrays. Lavas from the adjacent Western Volcanic Zone and the Eastern Volcanic Zone define oblique linear arrays that converge on a common local end-member that is not involved in the magmatism of the Northern Volcanic Zone. Therefore, there is a distinct NE-SW compositional heterogeneity within the Icelandic mantle.work was funded primarily by the Danish National Research Foundation through a grant to the former Danish Lithosphere Centre, with additional funding from the University of Iowa for the oxygen isotope analyses

Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer:Two externally validated nomograms

Introduction Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations. Methods 495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n = 214, patients treated in one hospital) and an external validation cohort n = 281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (<3 months) and long-term survival (>12 months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort. Results Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p < 0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC = 0.70 versus range AUCs = 0.51–0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1 year survival statistically significantly better (p < 0.05) than the favorable groups of four models (range AUCs = 0.57–0.61), except for the SIR (AUC = 0.64, p = 0.34). The models are available on www.predictcancer.org. Conclusion The nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice

Primary carbonatite melt from deeply subducted oceanic crust

Partial melting in the Earth's mantle plays an important part in generating the geochemical and isotopic diversity observed in volcanic rocks at the surface. Identifying the composition of these primary melts in the mantle is crucial for establishing links between mantle geochemical 'reservoirs' and fundamental geodynamic processes. Mineral inclusions in natural diamonds have provided a unique window into such deep mantle processes. Here we provide experimental and geochemical evidence that silicate mineral inclusions in diamonds from Juina, Brazil, crystallized from primary and evolved carbonatite melts in the mantle transition zone and deep upper mantle. The incompatible trace element abundances calculated for a melt coexisting with a calcium-titanium-silicate perovskite inclusion indicate deep melting of carbonated oceanic crust, probably at transition-zone depths. Further to perovskite, calcic-majorite garnet inclusions record crystallization in the deep upper mantle from an evolved melt that closely resembles estimates of primitive carbonatite on the basis of volcanic rocks. Small-degree melts of subducted crust can be viewed as agents of chemical mass-transfer in the upper mantle and transition zone, leaving a chemical imprint of ocean crust that can possibly endure for billions of years.4 page(s