IFI35, mir-99a and HCV Genotype to Predict Sustained Virological Response to Pegylated-Interferon Plus Ribavirin in Chronic Hepatitis C

International audienceAlthough, the treatment of chronic hepatitis C (CHC) greatly improved with the use of direct antiviral agents, pegylated-interferon (PEG-IFN) plus ribavirin remains an option for many patients, worldwide. The intra-hepatic level of expression of interferon stimulated genes (ISGs) and the rs12979860 CC genotype located within IFNL3 have been associated with sustained virological response (SVR), in patients with CHC. The aim of the study was to identify micro-RNAs associated with SVR and to build an accurate signature to predict SVR. Pre-treatment liver biopsies from 111 patients, treated with PEG-IFN plus ribavirin, were studied. Fifty-seven patients had SVR, 36 non-response (NR) and 18 relapse (RR). The expression of 851 human miRNAs and 30 selected mRNAs, including ISGs, was assessed by RT-qPCR. In the first group of patients (screen), 20 miRNAs out of the 851 studied were deregulated between NRs and SVRs. From the 4 miRNAs validated (mir-23a, mir-181a*, mir-217 and mir-99a), in the second group of patients (validation), 3 (mir-23a, mir-181a* and mir-99a) were down-regulated in NRs as compared to SVRs. The ISGs, studied, were accumulated in SVRs and IFNL3 rs12979860 CT/TT carriers compared respectively to NRs and CC carriers. Combining, clinical data together with the expression of selected genes and micro-RNAs, we identified a signature (IFI35, mir-99a and HCV genotype) to predict SVR (AUC:0.876) with a positive predictive value of 86.54% with high sensibility (80%) and specificity (80.4%). This signature may help to characterize patients with low chance to respond to PEG-IFN/ribavirin and to elucidate mechanisms of NR

Marine anticancer agents: An overview with a particular focus on their chemical classes

UID/Multi/04378/2019 IF/00700/2014 grant number 216Z167 grant RTA 2015-00010-C03-02 No. PBA/MB/16/01 PDOC/19/02/01The marine environment is a rich source of biologically active molecules for the treatment of human diseases, especially cancer. The adaptation to unique environmental conditions led marine organisms to evolve different pathways than their terrestrial counterparts, thus producing unique chemicals with a broad diversity and complexity. So far, more than 36,000 compounds have been isolated from marine micro- and macro-organisms including but not limited to fungi, bacteria, microalgae, macroalgae, sponges, corals, mollusks and tunicates, with hundreds of new marine natural products (MNPs) being discovered every year. Marine-based pharmaceuticals have started to impact modern pharmacology and different anti-cancer drugs derived from marine compounds have been approved for clinical use, such as: cytarabine, vidarabine, nelarabine (prodrug of ara-G), fludarabine phosphate (pro-drug of ara-A), trabectedin, eribulin mesylate, brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, belantamab mafodotin, plitidepsin, and lurbinectedin. This review focuses on the bioactive molecules derived from the marine environment with anticancer activity, discussing their families, origin, structural features and therapeutic use.publishersversionpublishe

The R136 star cluster hosts several stars whose individual masses greatly exceed the accepted 150 Msun stellar mass limit

Spectroscopic analyses of H-rich WN5-6 stars within the young star clusters NGC 3603 and R136 are presented, using archival HST & VLT spectroscopy, & high spatial resolution near-IR photometry. We derive high T* for the WN stars in NGC 3603 (T*~42+/-2 kK) & R136 (T*~53+/-3 kK) plus clumping-corrected dM/dt ~ 2-5x10^-5 Msun/yr which closely agree with theoretical predictions. These stars make a disproportionate contribution to the global budget of their host clusters. R136a1 alone supplies ~7% of N(LyC) of the entire 30 Dor region. Comparisons with stellar models calculated for the main-sequence evolution of 85-500 Msun suggest ages of ~1.5 Myr & M_init in the range 105 - 170 Msun for 3 systems in NGC 3603, plus 165-320 Msun for 4 stars in R136. Our high stellar masses are supported by dynamical mass determinations for the components of NGC 3603 A1. We consider the predicted L_X of the R136 stars if they were close, colliding wind binaries. R136c is consistent with a colliding wind binary system. However, short period, colliding wind systems are excluded for R136a WN stars if mass ratios are of order unity. Widely separated systems would have been expected to harden owing to early dynamical encounters with other massive stars in such a dense environment. From simulated star clusters, whose constituents are randomly sampled from the Kroupa IMF, both clusters are consistent with a tentative upper mass limit of ~300 Msun. The Arches cluster is either too old, exhibits a deficiency of very massive stars, or more likely stellar masses have been underestimated - M_init for the most luminous stars in the Arches cluster approach 200 Msun according to contemporary stellar & photometric results. The potential for stars greatly exceeding 150 Msun within metal-poor galaxies suggests that such pair-instability SNe could occur within the local universe, as has been claimed for SN 2007bi (abridged).Comment: 20 pages, 14 figures, accepted for MNRAS. Version with higher resolution figures is available from http://pacrowther.staff.shef.ac.uk/R136.pdf See also http://www.eso.org/public/news/eso1030/ from Wed 21 from noon (CEST

Using Pharmacokinetic and Viral Kinetic Modeling To Estimate the Antiviral Effectiveness of Telaprevir, Boceprevir, and Pegylated Interferon during Triple Therapy in Treatment-Experienced Hepatitis C Virus-Infected Cirrhotic Patients.: Effectiveness of triple therapy in cirrhotic patients

International audienceTriple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P = 0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P = 0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P = 0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P = 0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients

The essentials of marine biotechnology.

Coastal countries have traditionally relied on the existing marine resources (e.g., fishing, food, transport, recreation, and tourism) as well as tried to support new economic endeavors (ocean energy, desalination for water supply, and seabed mining). Modern societies and lifestyle resulted in an increased demand for dietary diversity, better health and well-being, new biomedicines, natural cosmeceuticals, environmental conservation, and sustainable energy sources. These societal needs stimulated the interest of researchers on the diverse and underexplored marine environments as promising and sustainable sources of biomolecules and biomass, and they are addressed by the emerging field of marine (blue) biotechnology. Blue biotechnology provides opportunities for a wide range of initiatives of commercial interest for the pharmaceutical, biomedical, cosmetic, nutraceutical, food, feed, agricultural, and related industries. This article synthesizes the essence, opportunities, responsibilities, and challenges encountered in marine biotechnology and outlines the attainment and valorization of directly derived or bio-inspired products from marine organisms. First, the concept of bioeconomy is introduced. Then, the diversity of marine bioresources including an overview of the most prominent marine organisms and their potential for biotechnological uses are described. This is followed by introducing methodologies for exploration of these resources and the main use case scenarios in energy, food and feed, agronomy, bioremediation and climate change, cosmeceuticals, bio-inspired materials, healthcare, and well-being sectors. The key aspects in the fields of legislation and funding are provided, with the emphasis on the importance of communication and stakeholder engagement at all levels of biotechnology development. Finally, vital overarching concepts, such as the quadruple helix and Responsible Research and Innovation principle are highlighted as important to follow within the marine biotechnology field. The authors of this review are collaborating under the European Commission-funded Cooperation in Science and Technology (COST) Action Ocean4Biotech – European transdisciplinary networking platform for marine biotechnology and focus the study on the European state of affairs

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

Coexistence of Hepatitis B Surface Antigen (HBs Ag) and Anti-HBs Antibodies in Chronic Hepatitis B Virus Carriers: Influence of “a” Determinant Variants

In chronic hepatitis B (CHB), the persistence of hepatitis B surface antigen (HBs Ag) is sometimes associated with antibodies (Ab) to HBs (anti-HBs). To assess the hypothesis of the selection of HBs Ag immune escape variants in CHB patients, the variability of the HBV S gene was determined for patients persistently carrying both HBs Ag and anti-HBs antibodies and patients solely positive for HBs Ag. We selected 14 patients who presented both markers (group I) in several consecutive samples and 12 patients positive for HBs Ag only (group II). The HBs Ag-encoding gene was amplified and cloned, and at least 15 clones per patient were sequenced and analyzed. The number of residue changes within the S protein was 2.7 times more frequent for group I than for group II patients and occurred mostly in the “a” determinant of the major hydrophilic region (MHR), with 9.52 versus 2.43 changes per 100 residues (P = 0.009), respectively. Ten patients (71%) from group I, but only three (25%) from group II, presented at least two residue changes in the MHR. The most frequent changes in group I patients were located at positions s145, s129, s126, s144, and s123, as described for immune escape variants. In CHB patients, the coexistence of HBs Ag and anti-HBs Ab is associated with an increase of “a” determinant variability, suggesting a selection of HBV immune escape mutants during chronic carriage. The consequences of this selection process with regard to vaccine efficacy, diagnosis, and clinical evolution remain partially unknown