Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

Inhibidor de MNK1; OncologíaInhibidor de MNK1; OncologiaMNK1 inhibitor; OncologyTargeting the kinases MNK1 and MNK2 has emerged as a valuable strategy in oncology. However, most of the advanced inhibitors are acting in an adenosine triphosphate (ATP)-competitive mode, precluding the evaluation of different binding modes in preclinical settings. Using rational design, we identified and validated the 4,6-diaryl-pyrazolo[3,4-b]pyridin-3-amine scaffold as the core for MNK inhibitors. Signaling pathway analysis confirmed a direct effect of the hit compound EB1 on MNKs, and in line with the reported function of these kinases, EB1 only affects the growth of tumor but not normal cells. Molecular modeling revealed the binding of EB1 to the inactive conformation of MNK1 and the interaction with the specific DFD motif. This novel mode of action appears to be superior to the ATP-competitive inhibitors, which render the protein in a pseudo-active state. Overcoming this paradoxical activation of MNKs by EB1 represents therefore a promising starting point for the development of a novel generation of MNK inhibitors.This work was supported by the Instituto de Salud Carlos III (PI17/02247), (PI20/01687), and CIBERONC (CB16/12/00363). S.R.y.C. acknowledges support from the Generalitat de Catalunya (2017-9015-385045). E. Bou-Petit thanks the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya (2017 FI_B2 00139) and the European Social Funds for her predoctoral fellowship

The oral KIF11 inhibitor 4SC-205 exhibits antitumor activity and potentiates standard and targeted therapies in primary and metastatic neuroblastoma models

Inhibidor de KIF11; Terapias dirigidas; MetástasisInhibidor de KIF11; Teràpies dirigides; MetàstasiKIF11 inhibitor; Targeted therapies; MetastasisIn summary, our study provides a rationale for the future therapeutic integration in clinical trials of 4SC-205, an structurally distinct oral KIF11 inhibitor that shows potent antitumor activity in multiple preclinical neuroblastoma models and sensitizes neuroblastoma cells to standard chemotherapy and specific neuroblastoma-targeted therapies.The financial support for this research was provided by Instituto de Salud Calos III (PI20/00530 to Miguel F. Segura; PI20/01107 to Rosa Noguera; PI17/02248 and CPII18/00027 to Anna Santamaria; PI19/01320 to Alberto Villanueva); Ministerio de Educación, Cultura y Deporte (Grant no. FPU16/01099 to Marc Masanas). This work was also supported by the Asociación NEN (Nico contra el cancer infantil 2017–PVR00157)

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

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

A Novel Saliva-Based miRNA Signature for Colorectal Cancer Diagnosis

Càncer colorectal; MicroARN; SalivaCáncer colorrectal; MicroARN; SalivaColorectal cancer; MicroRNA; SalivaSalivary microRNAs (miRNAs) are of high interest as diagnostic biomarkers for non-oral cancer. However, little is known about their value for colorectal cancer (CRC) detection. Our study aims to characterize salivary miRNAs in order to identify non-invasive markers for CRC diagnosis. The screening of 754 miRNAs was performed in saliva samples from 14 CRC and 10 healthy controls. The differential expressed miRNAs were validated by RT-qPCR in 51 CRC, 19 adenomas and 37 healthy controls. Receiver operating characteristic (ROC) curves and logistic regression models were performed to analyze the clinical value of these miRNAs. Twenty-two salivary miRNAs were significantly deregulated in CRC patients vs. healthy individuals (p < 0.05) in the discovery phase. From those, five upregulated miRNAs (miR-186-5p, miR-29a-3p, miR-29c-3p, miR-766-3p, and miR-491-5p) were confirmed to be significantly higher in the CRC vs. healthy group (p < 0.05). This five-miRNA signature showed diagnostic value (72% sensitivity, 66.67% specificity, AUC = 0.754) to detect CRC, which was even higher in combination with carcinoembryonic antigen (CEA) levels. Overall, after the first global characterization of salivary miRNAs in CRC, a five-miRNA panel was identified as a promising tool to diagnose this malignancy, representing a novel approach to detect cancer-associated epigenetic alterations using a non-invasive strategy.This research was funded by Eugenio Rodríguez Pascual Foundation and the Galician society that participated in the Liquid Biopsy crowdfunding. L.M.-R is supported by AECC Foundation

Search for new physics with emerging jets in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search for ``emerging jets'' produced in proton-proton collisions at a center-of-mass energy of 13 TeV is performed using data collected by the CMS experiment corresponding to an integrated luminosity of 138 fb$^{-1}$. This search examines a hypothetical dark quantum chromodynamics (QCD) sector that couples to the standard model (SM) through a scalar mediator. The scalar mediator decays into an SM quark and a dark sector quark. As the dark sector quark showers and hadronizes, it produces long-lived dark mesons that subsequently decay into SM particles, resulting in a jet, known as an emerging jet, with multiple displaced vertices. This search looks for pair production of the scalar mediator at the LHC, which yields events with two SM jets and two emerging jets at leading order. The results are interpreted using two dark sector models with different flavor structures, and exclude mediator masses up to 1950 (1850) GeV for an unflavored (flavor-aligned) dark QCD model. The unflavored results surpass a previous search for emerging jets by setting the most stringent mediator mass exclusion limits to date, while the flavor-aligned results provide the first direct mediator mass exclusion limits to date

Search for new physics with emerging jets in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search for ``emerging jets'' produced in proton-proton collisions at a center-of-mass energy of 13 TeV is performed using data collected by the CMS experiment corresponding to an integrated luminosity of 138 fb$^{-1}$. This search examines a hypothetical dark quantum chromodynamics (QCD) sector that couples to the standard model (SM) through a scalar mediator. The scalar mediator decays into an SM quark and a dark sector quark. As the dark sector quark showers and hadronizes, it produces long-lived dark mesons that subsequently decay into SM particles, resulting in a jet, known as an emerging jet, with multiple displaced vertices. This search looks for pair production of the scalar mediator at the LHC, which yields events with two SM jets and two emerging jets at leading order. The results are interpreted using two dark sector models with different flavor structures, and exclude mediator masses up to 1950 (1850) GeV for an unflavored (flavor-aligned) dark QCD model. The unflavored results surpass a previous search for emerging jets by setting the most stringent mediator mass exclusion limits to date, while the flavor-aligned results provide the first direct mediator mass exclusion limits to date