Characteristic time in quasispecies evolution

Estudio del tiempo en que un fenotipo alcanza un estado estacionari

Characteristic time in quasispecies evolution

Estudio del tiempo en que un fenotipo alcanza un estado estacionari

PanDrugs: a novel method to prioritize anticancer drug treatments according to individual genomic data

BACKGROUND: Large-sequencing cancer genome projects have shown that tumors have thousands of molecular alterations and their frequency is highly heterogeneous. In such scenarios, physicians and oncologists routinely face lists of cancer genomic alterations where only a minority of them are relevant biomarkers to drive clinical decision-making. For this reason, the medical community agrees on the urgent need of methodologies to establish the relevance of tumor alterations, assisting in genomic profile interpretation, and, more importantly, to prioritize those that could be clinically actionable for cancer therapy. RESULTS: We present PanDrugs, a new computational methodology to guide the selection of personalized treatments in cancer patients using the variant lists provided by genome-wide sequencing analyses. PanDrugs offers the largest database of drug-target associations available from well-known targeted therapies to preclinical drugs. Scoring data-driven gene cancer relevance and drug feasibility PanDrugs interprets genomic alterations and provides a prioritized evidence-based list of anticancer therapies. Our tool represents the first drug prescription strategy applying a rational based on pathway context, multi-gene markers impact and information provided by functional experiments. Our approach has been systematically applied to TCGA patients and successfully validated in a cancer case study with a xenograft mouse model demonstrating its utility. CONCLUSIONS: PanDrugs is a feasible method to identify potentially druggable molecular alterations and prioritize drugs to facilitate the interpretation of genomic landscape and clinical decision-making in cancer patients. Our approach expands the search of druggable genomic alterations from the concept of cancer driver genes to the druggable pathway context extending anticancer therapeutic options beyond already known cancer genes. The methodology is public and easily integratable with custom pipelines through its programmatic API or its docker image. The PanDrugs webtool is freely accessible at http://www.pandrugs.org .The authors thank Joaquín Dopazo, Patricia León, and José Carbonell for kindly providing the modelled pathways employed in PanDrugs implementation; and Michael Tress for his helpful comments and suggestions in the earlier version of the manuscript.S

Fatty acids homeostasis during fasting predicts protection from chemotherapy toxicity.

Fasting exerts beneficial effects in mice and humans, including protection from chemotherapy toxicity. To explore the involved mechanisms, we collect blood from humans and mice before and after 36 or 24 hours of fasting, respectively, and measure lipid composition of erythrocyte membranes, circulating micro RNAs (miRNAs), and RNA expression at peripheral blood mononuclear cells (PBMCs). Fasting coordinately affects the proportion of polyunsaturated versus saturated and monounsaturated fatty acids at the erythrocyte membrane; and reduces the expression of insulin signaling-related genes in PBMCs. When fasted for 24 hours before and 24 hours after administration of oxaliplatin or doxorubicin, mice show a strong protection from toxicity in several tissues. Erythrocyte membrane lipids and PBMC gene expression define two separate groups of individuals that accurately predict a differential protection from chemotherapy toxicity, with important clinical implications. Our results reveal a mechanism of fasting associated with lipid homeostasis, and provide biomarkers of fasting to predict fasting-mediated protection from chemotherapy toxicity.General: We thank Prof. Jose Maria. Ordovas for his kind suggestions; nutritionists Helena Marcos-Pasero, Elena Aguilar-Aguilar and Isabel Espinosa-Salinas for their help with volunteers management; Rosa Serrano for her help with animal experiments; Susana Molina for her advice with PBMC isolation; Luisa Mariscal, Domingo Fernandez, Lola Martinez, Diego Megias, Patricia Gonzalez, Fernando Pelaez, Anabel Sanz, Carolina Pola, Celia de la Calle, Ana Ortega, Ana Sagrera, Jose Miguel Frade, Elena Lopez-Guadamillas, Maribel Munoz, Susana Llanos, Andres Fernandez, Aranzazu Sierra, Andres Lopez, Noemi Haro and Ildefonso Rodriguez for their excellent technical and scientific support. Work at the laboratory of P.J.F.M. is funded by the Ramon Areces Foundation, (CIVP18A3891), Asociacion Espanola contra el Cancer-AECC (SIRTBIO-LABAE18008FERN), a Ramon y Cajal Award from the Spanish Ministry of Science, Innovation and Universities (MICINN) (RYC-2017-22335), RETOS projects Program of MICINN (SAF2017-85766-R) and the Portuguese Foundation for Science and Technology (FCT-MCTES, SFRH/BD/124022/2016). Work at the laboratory of ARM was funded by the MICINN (PID2019-110183RB-C21), Regional Government of Community of Madrid (P2018/BAA-4343-ALIBIRD2020-CM) and the Ramon Areces Foundation. Work at the laboratory of A.D.R. Funded by the Comunidad de Madrid-Talento Grant 2018-T1/BMD-11966 and the MICINN PID-2019-106893RA-100. Work at the laboratory of L.D. is funded by projects from the Health Research Fund (ISCIII FIS PI14/01374 and FISPI17/00508) and from a Manuel de Oya research fellowship from the Beer and Health Foundation. Work at the laboratory of A.E. is funded by a Ramon y Cajal Award from MICINN (RYC-2013-13546) and RETOS projects Program of the MICINN, co-funded by the European Regional Development Fund (ERDF) (SAF2015-67538-R). Work in the laboratory of M.S. was funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and the "laCaixa" Foundation.S

Potential Benefits of Sequential Inhibitor-Mutagen Treatments of RNA Virus Infections

Lethal mutagenesis is an antiviral strategy consisting of virus extinction associated with enhanced mutagenesis. The use of non-mutagenic antiviral inhibitors has faced the problem of selection of inhibitor-resistant virus mutants. Quasispecies dynamics predicts, and clinical results have confirmed, that combination therapy has an advantage over monotherapy to delay or prevent selection of inhibitor-escape mutants. Using ribavirin-mediated mutagenesis of foot-and-mouth disease virus (FMDV), here we show that, contrary to expectations, sequential administration of the antiviral inhibitor guanidine (GU) first, followed by ribavirin, is more effective than combination therapy with the two drugs, or than either drug used individually. Coelectroporation experiments suggest that limited inhibition of replication of interfering mutants by GU may contribute to the benefits of the sequential treatment. In lethal mutagenesis, a sequential inhibitor-mutagen treatment can be more effective than the corresponding combination treatment to drive a virus towards extinction. Such an advantage is also supported by a theoretical model for the evolution of a viral population under the action of increased mutagenesis in the presence of an inhibitor of viral replication. The model suggests that benefits of the sequential treatment are due to the involvement of a mutagenic agent, and to competition for susceptible cells exerted by the mutant spectrum. The results may impact lethal mutagenesis-based protocols, as well as current antiviral therapies involving ribavirin

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Interference by specific FMDV mutant combinations.

a<p>Interference was determined by measuring infectious progeny production after co-electroporation of pMT28 RNA alone (first row) or with mixtures of mutant FMDV RNAs (either Q2027A+MD or DMD+D3) in the absence (−) or presence (+) of guanidinium (GU) or ribavirin (R), as indicated. The origin of FMDV mutant RNAs and experimental procedures are detailed in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000658#s4" target="_blank">Materials and Methods</a>.</p>b<p>Interference (%) is defined as [titer pMT28–titer pMT28 (plus indicated components)/titer pMT28]×100. Values are the average of three determinations, at 3 h, 5 h and 6 h post-electroporation. Virus titers (expressed as percentage of the titer obtained for pMT28 alone) and standard deviations are given in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000658#ppat-1000658-g003" target="_blank">Figure 3</a>.</p>c<p>NA, not applicable; ND, not detectable.</p

Effect of guanidine (GU) concentration on the yield of progeny FMDV pMT28.

<p>Passages were carried out by infecting 2×10⁶ BHK-21cells with virus pMT28, in the presence of increasing concentrations of GU, as indicated in the boxes on the right. The initial multiplicity of infection (MOI) was 1–2 PFU/cell. For subsequent passages, 0.2 ml of supernatant from the previous passage were used, resulting in MOIs of 10⁻⁵ to 10⁻¹ PFU/cell in the presence of GU. Conditions for the infections, treatment with guanidine hydrochloride, and for determination of FMDV infectivity by plaque assay are detailed in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1000658#s4" target="_blank">Materials and Methods</a>. The discontinuous line indicates the limit of measurement of infectivity values.</p