Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study

ABSTRACTBackgroundEpigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.MethodsWe conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (9 single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs) and GrimAge (4 SNPs) on multiple cancers (i.e., breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N=34,710), and for cancer from the UK Biobank (N cases=2,671–13,879; N controls=173,493–372,016), FinnGen (N cases=719–8,401; N controls=74,685–174,006) and several international cancer genetic consortia (N cases=11,348–122,977; N controls=15,861–105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.ResultsMeta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR=1.12 per year increase in GrimAge acceleration, 95%CI 1.04–1.20, p=0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR=1.15, 95%CI 1.09–1.21, p=0.006), than rectal cancer (IVW OR=1.05, 95%CI 0.97–1.13, p=0.24). We also found evidence that higher GrimAge acceleration decreased the risk of prostate cancer (pooled IVW OR=0.93 per year increase in GrimAge acceleration, 95%CI 0.87–0.99, p=0.02). This was supported by MR sensitivity analyses, but did not replicate in MR analyses using data on parental history of prostate cancer in UK Biobank (IVW OR=1.00, 95%CI 0.96–1.04, p=1.00). Results were less consistent for associations between other epigenetic clocks and cancers.ConclusionsGrimAge acceleration may increase the risk of colorectal cancer. Additionally, there is more limited evidence that it may be protective against prostate cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.FundingFMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic’s Operational Programme “Competitiveness, Entrepreneurship & Innovation” (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019).RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer’s Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol.

Identification, validation and assessment of Multiple Occurrence Regional Landslide Events (MORLE) in Catalonia (Spain) during the last one hundred years.

<p>Landslides in the Pyrenees cause periodical damage to infrastructure and human lives. The European PyrMove project aims to develop cross-border methodologies to manage and reduce risk associated with these geological hazards. One of its approaches are the study of Multiple-Occurrence Regional Landslide Events (MORLE) generated by episodes of intense rainfalls that affect large areas. To prevent and manage MORLE crisis, an identification and categorization of the geological and meteorological factors determining the MORLEs that occurred in Catalonia during the 20th and 21st century were carried out, with special attention to the last 30 years. These events were contrasted to some relevant landslide events at worldwide scale. A new qualitative scale of magnitude multiple Regional Landslide event (mRL) has been conceived according two variables that provide the best reliability for the historical data: (1) the area of the affected region and (2) the magnitude of the largest inventoried landslide. To determine the magnitude of largest landslide we used the ICGC scale based on its size and the total mobilized energy (M). Finally, two MORLE that occurred in 1982 and 2003 in Catalonia have been studied in detail to collect basic information on geological phenomena. These preliminary works will make possible in the future to estimate the triggering precipitation thresholds that induce MORLE scenarios in Catalonia.</p><p>The magnitude scale of MORLE events allows contextualizing the Catalan MORLE in the World. In this approach, seventeen World’s MORLEs events have been described for this work. The main triggering factor of studied regional events has been earthquakes (56%) and intense rainfall or typhoons (44%). Their extension normally do not exceed 50,000 km2 and the number of landslides exceeds, in some cases, 50,000. MORLE’s magnitudes, are mostly 3 or higher, due to their large extension, and to the magnitude of the largest landslide, which normally reaches over the maximum degree within the established magnitude scale for landslides in Catalonia by ICGC (M). Damages and human losses have been difficult to quantify, however, at worldwide scale, most of the MORLEs recorded human losses (> 600 in some cases). The most catastrophic MORLE was in Wenchuan region, China, in October 2008, with more than 87,000 fatalities, 52,194 landslides and 410,000 km2 of affected regional area.</p><p>In Catalonia, 13 MORLEs have been registered from 1900 to present. Here, the main trigger factor has been intense precipitation and the affected areas usually do not exceed 10,000 km2. However, in some cases such as October 1982, which records the largest number of identified landslides (about 900), reached 20,000 km2. The magnitude of the largest event rarely exceeds category M4 in ICGC scale, being the majority category M3. Damages have been considerable in these events such as the most recent, triggered by Gloria storm in January 2020. For Catalonia, three general characteristics are notable: (1) East storm situations are the main generators of MORLE’s; (2) MORLEs usually reach magnitudes mRL3 o mRL4.</p><p>This work has been supported by the European Commission under the Interreg V-A-POCTEFA programme (grant no. PyrMove - EFA364/19).</p>

Planetary Terrestrial Analogues Library (PTAL) a novel database to support rover missions to Mars

<p>NASA/Mars2020 and ESA/ExoMars missions will look for traces of present or past life on Mars. To do so, both Perseverance and Rosalind Franklin rovers have been equipped with a wide set of spectroscopic systems to investigate the geochemistry and mineralogy of Martian rocks and soils. As spectroscopic techniques are acquiring an increasing importance in the field of Mars exploration, many research groups are trying to estimate and optimize their potential scientific return by carrying out representative analytical studies in the laboratory.</p><p>In this framework, PTAL is a research project founded by the European Commission through the H2020 program, which is aimed to provide the scientific community with a novel library of terrestrial analogue materials that have been selected based on their similarity to well-known Martian geological contexts. Planned to be released to public on January 2022, the PTAL platform (http://erica.uva.es/PTAL/) will provide future users with access to complementary spectroscopic and diffractometric data gathered from over 100 terrestrial analogues.</p><p>In detail, the XRD analysis of each analogue was carried out to gather a reliable overview of samples mineralogy. Then, LIBS, IR and Raman spectrometers were used to collect additional elemental and molecular data, these being the key analytical tools onboard NASA/Perseverance and ESA/Rosalind Franklin rovers. Beside the use of commercial spectrometers, the RLS ExoMars Simulator, the MicrOmega-Flight (FS) (Spare Model) and the ChemCam-FS were also employed to collect LIBS, Raman and NIR spectra (respectively) qualitatively comparable to those that will soon gathered on Mars.</p><p>In addition to analytical data, the PTAL platform will also provide direct access to a dedicated software (SpectPro) for spectral visualization and treatment [1]</p><p>To conclude, future users can also request physical access to the terrestrial analogues, so that the data contained in the PTAL library can be combined with further analysis in the laboratory.</p><p>To obtain further information about the PTAL project, please use the QR code provided in Figure 01.</p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gepj.c1afd2953bff50778920161/sdaolpUECMynit/12UGE&app=m&a=0&c=d612978c3e8bf727a0ba9991a9929b9d&ct=x&pn=gepj.elif&d=1" alt="" width="165" height="165"></p><p>Figure 01: PTAL QR code</p><p><strong>Acknowledgements</strong>: This work is financed through the European Research Council in the H2020- COMPET-2015 programme (grant 687302) and the Ministry of Economy and Competitiveness (MINECO, grant PID2019-107442RB-C31).</p><p><strong>References:</strong> [1] Saiz J. et al., (2019) EGU general Assembly, 21, 17904.</p>

Patient and public involvement in a UK National Institute for Health Research Programme Grant for Applied Research: experiences from the Chronic Headache Education and Self-management Study (CHESS)

Background: Patient and public involvement (PPI) plays a crucial role in ensuring research is carried out in conjunction with the people that it will impact upon. In this article, we present our experiences and reflections from working collaboratively with patients and public through the lifetime of an National Institute for Health Research (NIHR) programme grant; the Chronic Headache Education and Self-management Study (CHESS) which took place between 2015 and 2020. PPI over the course of CHESS: We worked closely with three leading UK migraine charities and a lay advisory group throughout the programme. We followed NIHR standards and used the Guidance for Reporting Involvement of Patients and the Public checklist. We consulted our PPI contacts using a variety of methods depending on the phase of the study and the nature of the request. This included emails, discussions, and face-to-face contact. PPI members contributed throughout the study in the programme development, in the grant application, ethics documentation, and trial oversight. During the feasibility study; in supporting the development of a classification interview for chronic headache by participating in a headache classification conference, assessing the relevance, and acceptability of patient-reported outcome measures by helping to analyse cognitive interview data, and testing the smartphone application making suggestions on how best to present the summary of data collected for participants. Due to PPI contribution, the content and duration of the study intervention were adapted and a Delphi study with consensus meeting developed a core outcome set for migraine studies. Conclusions: The involvement of the public and patients in CHESS has allowed us to shape its overall design, intervention development, and establish a core outcome set for future migraine studies. We have reflected on many learning points for the future application of PPI.

Pacemaker lead-induced progression of primary vs. secondary tricuspid regurgitation

Background Currently no data are available whether the implantation of right ventricular (RV) pacemaker (PM) lead worsens preexisting primary or secondary (functional due to RV dilatation, RVD) tricuspid regurgitation (TR). Purpose The aim of the present retrospective analysis was to assess TR after PM implantation with a RV lead. Methods Patients with PM implantation (n=990) were enrolled if they had routine echocardiography including assessment of TR before first implantation and immediately after. RVD and severity of TR were characterized visually. Based on RVD in baseline echocardiography, patients were divided into 2 groups: with primary TR (without preexisting RVD, n=743) or secondary TR (with preexisting RVD, n=243). Results Lead-induced worsening of TR was present in both groups (Table 1). Progression from mild/moderate to severe TR was observed in 6.7% of patients with primary TR, compared to 25.6% of patients with secondary TR (P=0.001). Using an ordinal regression model, the probability to progress to severe TR with primary TR was 14.8% (95% CI 11.0%-19.7%), compared to 41.6% (95% CI 40.3%-42.8%) with secondary TR (P<0.001). Conclusion Preexisting secondary TR was associated with higher rates of lead-induced progression to severe TR compared to primary TR. Leadless pacing or tricuspid valve clipping post-PM implantation could be an option for patients with preexisting secondary TR and indication for a PM. Table 1. Patient characteristics. Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This study was supported by the European Union's Horizon 2020 Future and Emerging Technologies Programme [Grant number 732170].

Sub-seasonal Monsoon Onset forecasting over West Africa

<p>Skilful onset forecasts are highly sought after in West Africa, due to the importance of monsoon onset for agriculture, disease prevalence and energy provision. With research on the sub-seasonal timescale bridging the gap between weather and seasonal forecasts, sub-seasonal forecasts may provide useful information in the period preceding monsoon onset. This study explores sub-seasonal monsoon onset forecasts over West Africa using three operational ensemble prediction systems (ECMWF, UKMO, and NCEP) from the Sub-seasonal to Seasonal (S2S) prediction project database in order to determine the spatial scale and lead time at which sub-seasonal forecasts can provide useful monsoon onset information. Current research and operational methods of determining onset are identified and compared. The effect of spatial averaging on onset forecasting and skill is explored by comparing regional [Coast, Forest, Transition and North] and local forecasts at 4 major cities over Ghana.</p><p> </p><p>‘This work was supported by UK Research and Innovation as part of the Global Challenges Research Fund, African SWIFT programme, grant number NE/P021077/1’</p>

Contribution of tree stem and canopy fluxes to the CH4 budget of a boreal birch and spruce forest

<p>Upland forest soils are typically a net methane (CH<sub>4</sub>) sink, while trees may act as CH<sub>4</sub> sources. Studies on tree CH<sub>4</sub> exchange in boreal forests, especially regarding canopies, are rare. We aimed to quantify the contribution of trees to the forest CH<sub>4</sub> budget during spring leaf-out period and to reveal the role of microbes in the CH<sub>4</sub> exchange of trees. We measured stem and shoot fluxes of two common boreal tree species at a fen and at an upland site at Hyytiälä, southern Finland, together with soil CH<sub>4</sub> flux, environmental variables and the abundances methanogens and methanotrophs within the forest. Both birch (<em>Betula pubescens</em>) and spruce (<em>Picea abies</em>) trees emitted CH<sub>4</sub> from their aboveground surfaces, with significantly higher stem emissions detected from the birch and higher shoot emissions from the spruce. The shoot CH<sub>4</sub> exchange had no clear link to the vertical profile of the canopy or the progress of the leaf-out. The stem CH<sub>4</sub> emissions from birches at the fen were high (mean 45 µg h<sup>−</sup><sup>1</sup> m<sup>−</sup><sup>2</sup>) and decreased drastically with stem height. Their dynamics followed soil temperature, suggesting the emitted CH<sub>4</sub> originated from the soil. A lack of similar pattern in the fen spruces and in the upland birch indicates other processes behind the stem CH<sub>4</sub> fluxes of these trees. The lack of detection of methanogens or methanotrophs in the aboveground plant tissues suggest that the observed tree-derived CH<sub>4 </sub>fluxes were not induced by these microbes. The emitted CH<sub>4</sub> from the tree stems may, however, be produced microbially in the soil indicating that physiological differences in tree anatomy or adaptation to different belowground conditions might be a key factor explaining the differences between the tree species.</p><p>Acknowledgements: This research was supported Academy of Finland (288494, 2884941), National Centre of Excellence (272041), ICOS-FINLAND (281255), Helsinki Institute of Life Science (HiLIFE), Czech Science Foundation (17-18112Y) and National Sustainability Program I (LO1415), and the European Research Council (ERC) under Horizon 2020 research and innovation programme, grant agreement No (757695).</p>