Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis

Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.Susan L. Heatley, Elyse C. Page, Laura N. Eadie, Barbara J. McClure, Jacqueline Rehn, David T. Yeung, Michael Osborn, Tamas Revesz, Maria Kirby, and Deborah L. Whit

A Theoretical Model of a Molecular-Motor-Powered Pump

The motion of a cylindrical bead in a fluid contained within a two-dimensional channel is investigated using the boundary element method as a model of a biomolecular-motor-powered microfluidics pump. The novelty of the pump lies in the use of motor proteins (kinesin) to power the bead motion and the few moving parts comprising the pump. The performance and feasibility of this pump design is investigated using two model geometries: a straight channel, and a curved channel with two concentric circular walls. In the straight channel geometry, it is shown that increasing the bead radius relative to the channel width, increases the flow rate at the expense of increasing the force the kinesins must generate in order to move the bead. Pump efficiency is generally higher for larger bead radii, and larger beads can support higher imposed loads. In the circular channel geometry, it is shown that bead rotation modifies the force required to move the bead and that shifting the bead inward slightly reduces the required force. Bead rotation has a minimal effect on flow rate. Recirculation regions, which can develop between the bead and the channel walls, influence the stresses and force on the bead. These results suggest this pump design is feasible, and the kinesin molecules provide sufficient force to deliver pico- to atto- l/s flows.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44478/1/10544_2005_Article_6168.pd

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

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

Evaluation of two cyclic di-peptides as inhibitors of CCL2 induced chemotaxis

Monocyte chemoattractant protein (CCL2) plays a major role in the recruitment of monocytes during inflammation. In this study we analysed properties of synthetic CCL2 inhibitors in inhibiting CCL2 mediated monocyte migration. Using trans-endothelial chemotaxis assays compounds C1 and C5 were found to significantly reduce CCL2 mediated migration. Flow based adhesion assays showed reduction in adhesion to VCAM-1 in the presence of 10 nM CCL2 and 50 μM C5 (p < 0.05). Further studies with these compounds can aid in their development as anti-inflammatory therapies

AAC Hodge Canada Western Red Spring wheat

AAC Hodge (BW1069) is a hollow-stemmed, awned and high yielding Canada Western Red Spring (CWRS) wheat cultivar suited to the growing conditions in Western Canada. AAC Hodge was 6% higher yielding than AAC Viewfield, the highest yielding check in the Central Bread Wheat Cooperative (CBWC) registration trials (2017-2019). Within the same test, AAC Hodge was 16% higher yielding than Carberry. AAC Hodge matured 1 d earlier than Carberry and 2 d later than Unity; Unity is the earliest maturing check in the eastern prairie growing conditions. AAC Hodge was 7 cm shorter with better lodging resistance than Unity. The lodging score for AAC Hodge was lower than the mean of the checks. The test weight of AAC Hodge was similar to the mean of the checks. Over the 3 yr of testing (2017-2019), the 1000-kernel weight of AAC Hodge was equal to, or higher than all the checks. The grain protein content of AAC Hodge was equal to that of AAC Viewfield. AAC Hodge was rated moderately resistant to Fusarium head blight (FHB; Fusarium graminearum Schwabe) and resistant to leaf rust (Puccinia triticina Erikss.), stripe rust (Puccinia striiformis Westend), stem rust (Puccinia graminis Pers. f. sp. tritici Eriks. E. Henn), and common bunt [Tilletia caries (DC) Tul. C. Tul.]. AAC Hodge ranged from resistant to moderately susceptible for its reaction to the Ug99 family of stem rusts. AAC Hodge was resistant to orange wheat blossom midge (OBWM) (Sitodiplosis mosellana Ghin). AAC Hodge was registered under the CWRS class.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Planning applications for food superstores 1960–86: Great Britain and South Wales

The development and implications of food superstores in Great Britain have been the focus of much study. Most analysis and research however has had the drawback of being based solely on successful superstore applications (i.e. trading stores). A recent example of such work has appeared in this journal (Guy, 1988). It is argued here however that such analyses provide an incomplete understanding of spatial strategies, planning policy effectiveness and the development of superstores. A better understanding is afforded through an analysis of all superstore applications, i.e. applications which are unsuccessful as well as those that succeed. A database for planning applications for superstores is used here to provide first an introductory analysis of superstore development processes in Great Britain and to a lesser extent, Wales, and secondly a critical analysis of Guy's(1988) study of superstore development in South Wales