Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.

N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment

Patients and relatives as auditors of safe practices in oncology and hematology day hospitals

Background When there is a gap in professionals’ adherence to safe practices during cancer treatment, the consequences can be serious. Identifying these gaps in order to enable improvements in patient safety can be a challenge. This study aimed to assess if cancer patients and their relatives can be given the skills to audit reliably four safe practices, and to explore whether they are willing to play this new role. Methods We recruited 136 participants in 2018, from the oncology and haematology day hospital of a tertiary hospital in Spain. Patient identification, hand hygiene, blood or chemotherapy identification, and side effects related to transfusion and chemotherapy, were the safe practices selected for evaluation. The study comprised two parts: an interventional educational program and a cross-sectional design to collect data and assess to what degree participants are able and willing to be auditors depending on their characteristics using multivariate logistic regression models. A participant’s auditing skill were assessed pre and post the educational intervention. Results The model was seeking predictors of being a good auditor. 63 participants (46.3%) were classified as good auditors after the training. To have younger age, higher educational level and to have had an experience of an adverse event were associated with a higher probability of being a good auditor. Additionally, 106 (77.9%) participants said that they would like to audit anonymously the professionals’ compliance of at least three of four safe practices. The willingness to audit safe practices differed depending on the safe practice but these differences did not reach statistical significance. Conclusions The data gathered by patients and relatives acting as auditors can provide healthcare organizations with valuable information about safety and quality of care that is not accessible otherwise. This new role provides an innovative way to engage patients and their families’ in healthcare safety where other methods have not had success. The paper sets out the methods that healthcare organizations need to undertake to enrol and train patients and relatives in an auditor role

Tonic and reflex cardiovascular autonomic control in trained-female rats

The effects of exercise training on cardiovascular and autonomic functions were investigated in female rats. After an aerobic exercise training period (treadmill: 5 days/week for 8 weeks), conscious female Wistar (2 to 3 months) sedentary (S, N = 7) or trained rats (T, N = 7) were cannulated for direct arterial pressure (AP) recording in the non-ovulatory phases. Vagal (VT) and sympathetic tonus (ST) were evaluated by vagal (atropine) and sympathetic (propranolol) blockade. Baroreflex sensitivity was evaluated by the heart rate responses induced by AP changes. Cardiopulmonary reflex was measured by the bradycardic and hypotensive responses to serotonin. Resting bradycardia was observed in T (332 ± 7 bpm) compared with S animals (357 ± 10 bpm), whereas AP did not differ between groups. T animals exhibited depressed VT and ST (32 ± 7 and 15 ± 4 bpm) compared to S animals (55 ± 5 and 39 ± 10 bpm). The baroreflex and cardiopulmonary bradycardic responses were lower in T (-1.01 ± 0.27 bpm/mmHg and -17 ± 6 bpm) than in the S group (-1.47 ± 0.3 bpm/mmHg and -41 ± 9 bpm). Significant correlations were observed between VT and baroreflex (r = -0.72) and cardiopulmonary (r = -0.76) bradycardic responses. These data show that exercise training in healthy female rats induced resting bradycardia that was probably due to a reduced cardiac ST. Additionally, trained female rats presented attenuated bradycardic responses to baro- and cardiopulmonary receptor stimulation that were associated, at least in part, with exercise training-induced cardiac vagal reduction

Environmental Impacts of an Alien Kelp Species (Undaria pinnatifida, Laminariales) along the Patagonian Coasts

Undariapinnatifida(Harvey) Suringar was recorded in Argentina for the first time in December 1992. Since then, it shows an invasive and competitive behavior, spreading quickly from the initial focus and increasing its population density. The first individuals were found attached to the port of Puerto Madryn, suggesting that the vector of introduction was the ballast water of cargo ships arriving to Golfo Nuevo from overseas. Since U. pinnatifidawas recorded, it has been spreading along the Argentina coasts, extending its range within and outside Golfo Nuevo, along the coasts of Argentina from Puerto Deseado (Santa Cruz province) to Mar del Plata (Buenos Aires province) far as 1850 kilometers from each other. The invasive condition of this species creates an awareness of the effects inflicted upon the indigenous biodiversity of this region, as well as, on the commercially-important benthic community structure. Moreover, the detachment of subtidal algae, especially during the summer, and its deposition upon the beach, have altered the sedimentary balance along the overall transverse beach profile. This effect, in addition with algal extraction by trucks mainly during tourist seasons, may increase beach erosion processes along Patagonian coasts.Fil: Bunicontro, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Marcomini, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Casas, Graciela Noemi. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico; Argentin