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Influenza is one of the leading causes of disease-related mortalities worldwide. Several strategies have been implemented during the past decades to hinder the replication cycle of influenza viruses, all of which have resulted in the emergence of resistant virus strains. The most recent example is baloxavir marboxil, where a single mutation in the active site of the target endonuclease domain of the RNA-dependent-RNA polymerase renders the recent FDA approved compound ∼1000-fold less effective. Raltegravir is a first-in-class HIV inhibitor that shows modest activity to the endonuclease. Here, we have used structure-guided approaches to create rationally designed derivative molecules that efficiently engage the endonuclease active site. The design strategy was driven by our previously published structures of endonuclease-substrate complexes, which allowed us to target functionally conserved residues and reduce the likelihood of resistance mutations. We succeeded in developing low nanomolar equipotent inhibitors of both wild-type and baloxavir-resistant endonuclease. We also developed macrocyclic versions of these inhibitors that engage the active site in the same manner as their 'open' counterparts but with reduced affinity. Structural analyses provide clear avenues for how to increase the affinity of these cyclic compounds.

Anthropogenic increases in nitrogen (N) and phosphorus (P) concentrations can strongly influence the structure and function of ecosystems. Even though lotic ecosystems receive cumulative inputs of nutrients applied to and deposited on land, no comprehensive assessment has quantified nutrient-enrichment effects within streams and rivers. We conducted a meta-analysis of published studies that experimentally increased concentrations of N and/or P in streams and rivers to examine how enrichment alters ecosystem structure (state: primary producer and consumer biomass and abundance) and function (rate: primary production, leaf breakdown rates, metabolism) at multiple trophic levels (primary producer, microbial heterotroph, primary and secondary consumers, and integrated ecosystem). Our synthesis included 184 studies, 885 experiments, and 3497 biotic responses to nutrient enrichment. We documented widespread increases in organismal biomass and abundance (mean response = +48%) and rates of ecosystem processes (+54%) to enrichment across multiple trophic levels, with no large differences in responses among trophic levels or between autotrophic or heterotrophic food-web pathways. Responses to nutrient enrichment varied with the nutrient added (N, P, or both) depending on rate versus state variable and experiment type, and were greater in flume and whole-stream experiments than in experiments using nutrient-diffusing substrata. Generally, nutrient-enrichment effects also increased with water temperature and light, and decreased under elevated ambient concentrations of inorganic N and/or P. Overall, increased concentrations of N and/or P altered multiple food-web pathways and trophic levels in lotic ecosystems. Our results indicate that preservation or restoration of biodiversity and ecosystem functions of streams and rivers requires management of nutrient inputs and consideration of multiple trophic pathways.

Conceptual models underpin river ecosystem research. However, current models focus on continuously flowing rivers and few explicitly address characteristics such as flow cessation and drying. The applicability of existing conceptual models to nonperennial rivers that cease to flow (intermittent rivers and ephemeral streams, IRES) has not been evaluated. We reviewed 18 models, finding that they collectively describe main drivers of biogeochemical and ecological patterns and processes longitudinally (upstream-downstream), laterally (channel-riparian-floodplain), vertically (surface water-groundwater), and temporally across local and landscape scales. However, perennial rivers are longitudinally continuous while IRES are longitudinally discontinuous. Whereas perennial rivers have bidirectional lateral connections between aquatic and terrestrial ecosystems, in IRES, this connection is unidirectional for much of the time, from terrestrial-to-aquatic only. Vertical connectivity between surface and subsurface water occurs bidirectionally and is temporally consistent in perennial rivers. However, in IRES, this exchange is temporally variable, and can become unidirectional during drying or rewetting phases. Finally, drying adds another dimension of flow variation to be considered across temporal and spatial scales in IRES, much as flooding is considered as a temporally and spatially dynamic process in perennial rivers. Here, we focus on ways in which existing models could be modified to accommodate drying as a fundamental process that can alter these patterns and processes across spatial and temporal dimensions in streams. This perspective is needed to support river science and management in our era of rapid global change, including increasing duration, frequency, and occurrence of drying.

BackgroundPaediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.MethodsThe Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.FindingsBetween July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.InterpretationSelumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.FundingNational Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.

Peritoneal metastasis (PM) from appendiceal cancer or colorectal cancer (CRC) has significant morbidity and limited survival. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a minimally invasive approach to treat PM. We aim to conduct a dose-escalation trial of mitomycin C (MMC)-PIPAC combined with systemic chemotherapy (FOLFIRI) in patients with PM from appendiceal cancer or CRC.

In this article, we give an overview of translational educational neuroscience (mind, brain, and education) in the United Kingdom. We consider the state of translation, describing respectively the state of the dialogue between researchers and educators, the state of evaluation of approaches to improve educational outcomes, and the state of innovation in research translation. We consider the teacher perspective. What do UK teachers think about educational neuroscience and its potential for informing classroom practice, and how do ideas about pedagogical approaches feature among their everyday concerns? We describe the results of a recent survey from a representative sample of over 1,000 UK teachers, and a case study of a UK high school teacher who employs educational neuroscience in his practice and what this entails. Lastly, we consider the policy perspective and assess the recent move by the UK government to introduce knowledge of cognitive science into initial and early‐career teacher training. In this article, we give an overview of translational educational neuroscience (mind, brain, and education) in the United Kingdom. We consider the state of translation, including the dialogue between researchers and educators, approaches to evaluation, and innovation in translating research into practice. We consider the teacher perspective, including the results of a survey of over 1,000 UK teachers on their views on educational neuroscience and how it relates to their classroom practice. And we consider the policy perspective, including the recent move by the UK government to introduce knowledge of cognitive science into initial and early‐career teacher training. [ABSTRACT FROM AUTHOR]

This letter to the editor published in Leukemia & Lymphoma discusses a case of acute undifferentiated leukemia (AUL) successfully treated with a novel combination therapy of FLAG-IDA and venetoclax. A 55-year-old female with AUL and high-risk genetic features achieved complete remission after induction treatment with FLAG-IDA + VEN. The patient experienced a complicated course but responded well to treatment, highlighting the potential efficacy of this regimen in AUL cases. The study emphasizes the importance of individualized treatment strategies for rare leukemia subtypes like AUL, which often have poor outcomes and limited treatment options. [Extracted from the article]

BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH-ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. © 2018 American Cancer Society.