Regulation of L1 expression and retrotransposition by melatonin and its receptor: implications for cancer risk associated with light exposure at night.

Expression of long interspersed element-1 (L1) is upregulated in many human malignancies. L1 can introduce genomic instability via insertional mutagenesis and DNA double-strand breaks, both of which may promote cancer. Light exposure at night, a recently recognized carcinogen, is associated with an increased risk of cancer in shift workers. We report that melatonin receptor 1 inhibits mobilization of L1 in cultured cells through downregulation of L1 mRNA and ORF1 protein. The addition of melatonin receptor antagonists abolishes the MT1 effect on retrotransposition in a dose-dependent manner. Furthermore, melatonin-rich, but not melatonin-poor, human blood collected at different times during the circadian cycle suppresses endogenous L1 mRNA during in situ perfusion of tissue-isolated xenografts of human cancer. Supplementation of human blood with exogenous melatonin or melatonin receptor antagonist during the in situ perfusion establishes a receptor-mediated action of melatonin on L1 expression. Combined tissue culture and in vivo data support that environmental light exposure of the host regulates expression of L1 elements in tumors. Our data imply that light-induced suppression of melatonin production in shift workers may increase L1-induced genomic instability in their genomes and suggest a possible connection between L1 activity and increased incidence of cancer associated with circadian disruption

Antiplasmodial and leishmanicidal activities of 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives.

Malaria and leishmaniasis are two of the World’s most important tropical parasitic diseases. Thirteen new 2-cyano-3-(4-phenylpiperazine-1-carboxamido) quinoxaline 1,4-dioxide derivatives (CPCQs) were synthesized and evaluated for their in vitro antimalarial and antileishmanial activity against erythrocytic forms of Plasmodium falciparum and axenic forms of Leishmania infantum. Their toxicity against VERO cells (normal monkey kidney cells) was also assessed. None of the tested compounds was efficient against Plasmodium, but two of them showed good activity against Leishmania. Toxicity on VERO was correlated with leishmanicidal properties

Safety and effectiveness of edoxaban in a real-world clinical setting: Two-year follow-up of the ETNA-AF-Europe study

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe OnBehalf ETNA-AF-Europe investigators Background Oral anticoagulation (OAC) for stroke prevention is essential in the management of patients with atrial fibrillation (AF). The assessment of OAC use in routine clinical care and the effects of this therapy on outcomes and safety are important. Purpose: We analysed two-year outcome data with adjudicated follow-up results in 13,417 patients with AF treated with edoxaban. Methods: ETNA-AF-Europe (Clinicaltrials.gov: NCT02944019) enrolled 13,417 consecutive patients with AF treated with edoxaban in 825 centres in 10 European countries and 2-year prospectively collected, real world data is presented. Results: Edoxaban was prescribed according to licence recommendations in 83.1% (n = 11,146) of patients (Table). Whilst three quarters of patients were prescribed edoxaban 60 mg (n = 10,248, 76.4%), the quarter prescribed edoxaban 30 mg were older (79.5 versus 71.8 years), had a higher stroke risk (CHA2DS2-VASc score: 3.9 versus 3.0) and a higher bleeding risk (HAS-BLED score: 2.9 versus 2.4). Thromboembolic and bleeding events were more common in patients receiving edoxaban 30 mg OD without differences in intracranial haemorrhage (ICH) (Figure). Patients prescribed a non-recommended dose of edoxaban had a numerically higher stroke risk (CHA2DS2-VASc score: 3.6 versus 3.1) with subsequent higher rates of ischemic stroke and mortality, however they also had higher bleeding rates, with the exception of ICH (table) despite a similar initial bleeding risk (HAS-BLED score: 2.7 versus 2.5). Conclusions: In this large, European data set reporting two-year outcomes on edoxaban therapy, no additional safety signals were observed and event rates were in line with those observed in ETNA-AF after 1 year and in ENGAGE AF-TIMI 48, re-affirming the safety and effectiveness of edoxaban licence recommendations in a real world setting of patients with AF. All key events of interest, other than intracranial haemorrhage, were numerically lower in patients prescribed the licenced recommended dose. Outcomes with rec. vs non-rec. dosesn (%/year [95%CI])Recommended dose (n = 11,146; 83.1%)Non-recommended dose (n = 2271; 16.9%)Any stroke/SEE138 (0.68 [0.57;0.80])31 (0.76 [0.51;1.07])Ischaemic stroke99 (0.48 [0.39;0.59])26 (0.63 [0.41; 0.93])Major bleeding189 (0.93 [0.80;1.07])49 (1.20 [0.89;1.59])Intracranial haemorrhage43 (0.21 [0.15;0.28])7 (0.17 [0.07;0.35])All-cause mortality729 (3.55 [3.30;3.82])208 (5.04 [4.38;5.78])CV mortality405 (1.97 [1.79;2.18])113 (2.74 [2.26;3.30])CI, confidence interval; CV, cardiovascular; rec., recommended; SEE, systemic embolic event.Abstract Figure. Annualised event rates at 2-year F

Characteristics of patients initiated on edoxaban in Europe: baseline data from edoxaban treatment in routine clinical practice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe)

Background Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have substantially improved anticoagulation therapy for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). The available routine care data have demonstrated the safety of different NOACs; however, such data for edoxaban are scarce. Here, we report baseline characteristics of 13,638 edoxaban-treated patients with AF enrolled between November 2016 and February 2018. Methods ETNA-AF-Europe is a multinational, multi-centre, post-authorisation, observational study conducted in 825 sites in 10 European countries. Patients will be followed up for four years. Results Overall, 13,980 patients were enrolled of which 342 patients were excluded from the analysis. Mean patient age was 73.6 years with an average creatinine clearance of 69.4 mL/min. 56.6% were male. The calculated CHA2DS2-VASc and HAS-BLED mean scores were 3.1 and 2.6, respectively. Overall, 3.3, 14.6 and 82.0% of patients had low (CHA2DS2-VASc = 0), intermediate (CHA2DS2-VASc = 1) and high (CHA2DS2-VASc≥2) risks of stroke, respectively. High-risk patients (those with prior stroke, prior major bleeding, prior intracranial bleed or CHA2DS2-VASc ≥4) comprised 38.4% of the overall population. For 75.1% of patients edoxaban was their first anticoagulant prescription, whilst 16.9% switched from a VKA and 8.0% from another NOAC. A total of 23.4% of patients in ETNA-AF-Europe received the reduced dose of edoxaban 30 mg. Overall, 83.8% of patients received an edoxaban dose in line with the criteria outlined in the label. Conclusion Edoxaban was predominantly initiated in older, often anticoagulation-naïve, unselected European patients with AF, with a good overall adherence to the approved label. Trial registration NCT02944019; Date of registration: October 24, 2016

Implantable cardioverter defibrillator therapy for primary prevention of sudden cardiac death in the real world: Main findings from the French multicentre DAI-PP programme (pilot phase)

This review summarizes the main findings of the French multicentre DAI-PP pilot programme, and discusses the related clinical and research perspectives. This project included retrospectively (2002–2012 period) more than 5000 subjects with structural heart disease who received an implantable cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death, and were followed for a mean period of 3 years. The pilot phase of the DAI-PP programme has provided valuable information on several practical and clinically relevant aspects of primary prevention ICD implantation in the real-world population, which are summarized in this review. This pilot has led to a prospective evaluation that started in May 2018, assessing ICD therapy in primary and secondary prevention in patients with structural and electrical heart diseases, with remote monitoring follow-up using a dedicated platform. This should further enhance our understanding of sudden cardiac death, to eventually optimize the field of preventative actions

Analysis of additivity and synergism in the anti-plasmodial effect of purified compounds from plant extracts

In the search for antimalarials from ethnobotanical origin, plant extracts are chemically fractionated and biological tests guide the isolation of pure active compounds. To establish the responsibility of isolated active compound(s) to the whole antiplasmodial activity of a crude extract, the literature in this field was scanned and results were analysed quantitatively to find the contribution of the pure compound to the activity of the whole extract. It was found that, generally, the activity of isolated molecules could not account on their own for the activity of the crude extract. It is suggested that future research should take into account the “drugs beside the drug”, looking for those products (otherwise discarded along the fractionation process) able to boost the activity of isolated active compounds