Synthesis and Evaluation of Cytostatic and Antiviral Activities of 3′ and 4′-Avarone Derivatives

A series of 3′ and 4′-substituted avarone derivatives were synthesized and tested in culture systems as antitumour and antiviral agents in comparison to avarol and avarone. 3′-alkylamino derivatives showed potent cytostatic activities against murine L1210 and human B (Raji) and T (C8166, H9) lymphoblast cells (ID50 range 1.7–3.7 μm). Avarol and avarone were six times less active. While none of the derivatives showed anti-human immunodeficiency virus (HIV) activity superior to that of the parent compounds, most of them, avarol and avarone included, were potent and selective inhibitors of poliovirus multiplication

Anatomical targets and expected outcomes of catheter-based ablation of atrial fibrillation in 2020.

Anatomical-based approaches, targeting either pulmonary vein isolation (PVI) or additional extra PV regions, represent the most commonly used ablation treatments in symptomatic patients with atrial fibrillation (AF) recurrences despite antiarrhythmic drug therapy. PVI remains the main anatomical target during catheter-based AF ablation, with the aid of new technological advances as contact force monitoring to increase safety and effective radiofrequency (RF) lesions. Nowadays, cryoballoon ablation has also achieved the same level of scientific evidence in patients with paroxysmal AF undergoing PVI. In parallel, electrical isolation of extra PV targets has progressively increased, which is associated with a steady increase in complex cases undergoing ablation. Several atrial regions as the left atrial posterior wall, the vein of Marshall, the left atrial appendage, or the coronary sinus have been described in different series as locations potentially involved in AF initiation and maintenance. Targeting these regions may be challenging using conventional point-by-point RF delivery, which has opened new opportunities for coadjuvant alternatives as balloon ablation or selective ethanol injection. Although more extensive ablation may increase intraprocedural AF termination and freedom from arrhythmias during the follow-up, some of the targets to achieve such outcomes are not exempt of potential severe complications. Here, we review and discuss current anatomical approaches and the main ablation technologies to target atrial regions associated with AF initiation and maintenance.This work was supported by the European Regional Development Fund, the Spanish Ministry of Science and Innovation (SAF2016- 80324-R), and the Fundación Interhospitalaria para la Investigación Cardiovascular (FIC). The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Science and Innovation and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Giulio La Rosa has received a fellowship grant from the joint program between the Heart Rhythm Association of the Spanish Society of Cardiology (ARC) and CNIC.S

Intron 4-5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4-5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR\u2009=\u20092.500, p\u2009=\u20090.015) and p63 (HR\u2009=\u20092.659, p\u2009=\u20090.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (-) cases (21 vs 14, p\u2009=\u20090.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p\u2009=\u20090.026), no angioinvasion (40.7% vs 71.0%, p\u2009=\u20090.015), lower Ki67 (50 vs 70%, p\u2009=\u20090.005), and PD-L1 expressions in both tumor (0 vs 3%, p\u2009=\u20090.021) and immune cells (0 vs 10%, p\u2009=\u20090.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients

Fruit Composition of Eggplant Lines with Introgressions from the Wild Relative S. incanum: Interest for Breeding and Safety for Consumption

[EN] The wild species Solanum incanum has been used as a donor parent for the development of a set of eggplant introgression lines (ILs), which are of interest for breeding for stress tolerances and relevant morpho-agronomic traits but could also be useful for breeding for fruit quality, due to the generally higher content in health-promoting compounds of S. incanum. The use of eggplant ILs with introgressions from S. incanum requires ensuring that glycoalkaloids levels are below safety limits. We evaluated 25 fruit composition traits, including proximate composition, sugars, acids, phenolics, glycoalkaloids, and minerals in a set of 16 eggplant ILs with S. incanum, both parents and the F-1, grown under two environments (open field and screenhouse). The results demonstrated that the parents were significantly different regarding most fruit composition traits. Large variation was found among the 16 ILs for all traits analyzed and a strong influence of the environment accounted for the variation of 17 out of the 25 traits evaluated. Although the S. incanum parent produced fruits with high levels of glycoalkaloids, the 16 ILs showed mean values of total glycoalkaloids below the currently accepted safety limit for human consumption (200 mg kg(-1) fresh weight). Overall, the ILs produced fruits that are safe for consumption, with nutritional and functional quality similar to the recipient parent. Furthermore, six putative QTLs were detected spread over chromosomes 3 for crude protein, 5 for malic and total acids, and 7 for chlorogenic acid and solamargine, and potential candidate genes were spotted for most of them, which provide new relevant information for eggplant breeding.This work was undertaken as part of the initiative "Adapting Agriculture to Climate Change: Collecting, Protecting and Preparing Crop Wild Relatives", which is supported by the Government of Norway. The project is managed by the Global Crop Diversity Trust with the Millennium Seed Bank of the Royal Botanic Gardens, Kew, and implemented in partnership with national and international gene banks and plant breeding institutes around the world. For further information see the project website: http://www.cwrdiversity.org/.Funding was also received from grants AGL2015-64755-R funded by MCIN/AEI/10.13039/501100011033 and by "ERDF A way of making Europe" and RTI-2018-094592-B-100 funded by MCIN/AEI/10.13039/501100011033, and from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 677379 (G2P-SOL project: Linking genetic resources, genomes, and phenotypes of Solanaceous crops). M.P. is grateful to the Spanish Ministerio de Ciencia e Innovacion for a post-doctoral grant with the Juan de la Cierva program (grant number IJC2019-039091-I from MCIN/AEI/10.1309/501100011033). P.G. is grateful to the Japan Society for the Promotion of Science for a post-doctoral grant (P19105, FY2019 JSPS Postdoctoral Fellowship for Research in Japan). E.R.-M. is grateful to the Spanish Ministerio de Economia, Industria y Competitividad for a pre-doctoral grant (grant number BES-2016-077482 from MCIN/AEI/10.1309/501100011033).Rosa-Martínez, E.; Adalid-Martinez, AM.; García-Martínez, MD.; Mangino, G.; Raigón Jiménez, MD.; Plazas Ávila, MDLO.; Gramazio, P.... (2022). Fruit Composition of Eggplant Lines with Introgressions from the Wild Relative S. incanum: Interest for Breeding and Safety for Consumption. Agronomy. 12(2):1-12. https://doi.org/10.3390/agronomy1202026611212

Mapping Technologies for Catheter Ablation of Atrial Fibrillation Beyond Pulmonary Vein Isolation

Catheter ablation remains the most effective and relatively minimally invasive therapy for rhythm control in patients with AF. Ablation has consistently shown a reduction of arrhythmia-related symptoms and significant improvement in patients’ quality of life compared with medical treatment. The ablation strategy relies on a well-established anatomical approach of effective pulmonary vein isolation. Additional anatomical targets have been reported with the aim of increasing procedure success in complex substrates. However, larger ablated areas with uncertainty of targeting relevant regions for AF initiation or maintenance are not exempt from the potential risk of complications and pro-arrhythmia. Recent developments in mapping tools and computational methods for advanced signal processing during AF have reported novel strategies to identify atrial regions associated with AF maintenance. These novel tools – although mainly limited to research series – represent a significant step forward towards the understanding of complex patterns of propagation during AF and the potential achievement of patient-tailored AF ablation strategies for the near future

3D active edge silicon sensors: Device processing, yield and QA for the ATLAS-IBL production

n/

Effects of the dose of erythropoiesis stimulating agents on cardiovascular events, quality of life, and health-related costs in hemodialysis patients: the clinical evaluation of the dose of erythropoietins (C.E. DOSE) trial protocol

<p>Abstract</p> <p>Background</p> <p>Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targeting higher hemoglobin levels with ESA causes an increased risk of adverse vascular outcomes. It is possible, but has never been formally tested in a randomized trial, that ESA dose rather than targeted hemoglobin concentration itself mediates the increased risk of adverse vascular outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial will assess the benefits and harms of a high versus a low fixed ESA dose for the management of anemia in patients with end stage kidney disease.</p> <p>Methods/Design</p> <p>This is a randomized, prospective open label blinded end-point (PROBE) trial due to enrol 2204 hemodialysis patients in Italy. Patients will be randomized 1:1 to 4000 IU/week versus 18000 IU/week of intravenous epoietin alfa or beta, or any other ESA in equivalent doses. The dose will be adjusted only if hemoglobin levels fall outside the 9.5-12.5 g/dL range. The primary outcome will be a composite of all-cause mortality, non fatal stroke, non fatal myocardial infarction and hospitalization for cardiovascular causes. Quality of life and costs will also be assessed.</p> <p>Discussion</p> <p>The C.E.DOSE study will help inform the optimal therapeutic strategy for the management of anemia of hemodialysis patients, improving clinical outcomes, quality of life and costs, by ascertaining the potential benefits and harms of different fixed ESA doses.</p> <p>Trial registration</p> <p>Clinicaltrials.gov NCT00827021</p

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201