BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications

Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs

BRAF V600E Mutations Are Common in Pleomorphic Xanthoastrocytoma: Diagnostic and Therapeutic Implications

Pleomorphic xanthoastrocytoma (PXA) is low-grade glial neoplasm principally affecting children and young adults. Approximately 40% of PXA are reported to recur within 10 years of primary resection. Upon recurrence, patients receive radiation therapy and conventional chemotherapeutics designed for high-grade gliomas. Genetic changes that can be targeted by selective therapeutics have not been extensively evaluated in PXA and ancillary diagnostic tests to help discriminate PXA from other pleomorphic and often more aggressive astrocytic malignancies are limited. In this study, we apply the SNaPshot multiplexed targeted sequencing platform in the analysis of brain tumors to interrogate 60 genetic loci that are frequently mutated in 15 cancer genes. In our analysis we detect BRAF V600E mutations in 12 of 20 (60%) WHO grade II PXA, in 1 of 6 (17%) PXA with anaplasia and in 1 glioblastoma arising in a PXA. Phospho-ERK was detected in all tumors independent of the BRAF mutation status. BRAF duplication was not detected in any of the PXA cases. BRAF V600E mutations were identified in only 2 of 71 (2.8%) glioblastoma (GBM) analyzed, including 1 of 9 (11.1%) giant cell GBM (gcGBM). The finding that BRAF V600E mutations are common in the majority of PXA has important therapeutic implications and may help in differentiating less aggressive PXAs from lethal gcGBMs and GBMs

The Global Alliance for Infections in Surgery : defining a model for antimicrobial stewardship-results from an international cross-sectional survey

Background: Antimicrobial Stewardship Programs (ASPs) have been promoted to optimize antimicrobial usage and patient outcomes, and to reduce the emergence of antimicrobial-resistant organisms. However, the best strategies for an ASP are not definitively established and are likely to vary based on local culture, policy, and routine clinical practice, and probably limited resources in middle-income countries. The aim of this study is to evaluate structures and resources of antimicrobial stewardship teams (ASTs) in surgical departments from different regions of the world. Methods: A cross-sectional web-based survey was conducted in 2016 on 173 physicians who participated in the AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections) project and on 658 international experts in the fields of ASPs, infection control, and infections in surgery. Results: The response rate was 19.4%. One hundred fifty-six (98.7%) participants stated their hospital had a multidisciplinary AST. The median number of physicians working inside the team was five [interquartile range 4-6]. An infectious disease specialist, a microbiologist and an infection control specialist were, respectively, present in 80.1, 76.3, and 67.9% of the ASTs. A surgeon was a component in 59.0% of cases and was significantly more likely to be present in university hospitals (89.5%, p <0.05) compared to community teaching (83.3%) and community hospitals (66.7%). Protocols for pre-operative prophylaxis and for antimicrobial treatment of surgical infections were respectively implemented in 96.2 and 82.3% of the hospitals. The majority of the surgical departments implemented both persuasive and restrictive interventions (72.8%). The most common types of interventions in surgical departments were dissemination of educational materials (62.5%), expert approval (61.0%), audit and feedback (55.1%), educational outreach (53.7%), and compulsory order forms (51.5%). Conclusion: The survey showed a heterogeneous organization of ASPs worldwide, demonstrating the necessity of a multidisciplinary and collaborative approach in the battle against antimicrobial resistance in surgical infections, and the importance of educational efforts towards this goal.Peer reviewe

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

PEGylated, NH₂‑Terminated PAMAM Dendrimers: A Microscopic View from Atomistic Computer Simulations

Poly­(amido amine) (PAMAM) dendrimers are promising nano­carriers in a wide range of biomedical applications including gene and drug delivery and as imaging agents. They have unique structural properties and are characterized by high size uniformity, low poly­dispersity, and a large number of modifiable surface groups. Drug–dendrimer systems are usually further modified through the conjugation of ligands in order to confer the carriers’ specific characteristics designed to enhance their efficacy. The chemistry and structure of the solvated ligand-conjugated dendrimer nanocarriers (DNCs) will dictate how they interact with the physio­logical environment and, therefore, their fate and function. Understanding the micro­structures of ligand-conjugated DNCs is, therefore, of great relevance within the context of drug delivery applications. In this work, we investigate the effect of poly­(ethylene glycol) (PEG) on the micro­structure of solvated, NH₂-terminated PAMAM DNCs using fully atomistic molecular dynamics simulations. Several variables including dendrimer generation (2–5), PEGylation density (0–50%), and PEG <i>M</i>_w (500 and 1000) were investigated. The results obtained showed a good match with available experimental results, including size as a function of dendrimer degeneration (G2NH₂–G5NH₂). No back-folding is observed for PAMAM dendrimers with generation lower than G5NH₂. G2NH₂ and G3NH₂ showed a dense-packed, nonglobular structure, and G4NH₂ and G5NH₂ have a segmented, “open” structure. Our results help settle a long-standing debate with respect to “back-folding” as the micro­structural information obtained here is reconciled with experimental results. PEGylation was found to influence the micro­structure in a different way, including an expected increase in the overall size of the DNCs, while not affecting much the solvation of unmodified terminal (primary) amines. It also serves to expand the core of dendrimers, reduce the surface charge, and change solvation behavior of different generation branching amines. We show that the micro­structure of a PEG layer with the same number of repeat units can be significantly altered by changing the grafting density and size of PEG. Potential consequences in the design of PEGylated dendrimers for drug delivery and targeting are discussed based on the obtained micro­structural information

Understanding Solvation in the Low Global Warming Hydrofluoroolefin HFO-1234ze Propellant

Hydrofluoroolefins (HFOs), with zero ozone-depleting effect and very low global warming potential, are considered to be the next-generation high-pressure working fluids. They have industrial relevance in areas including refrigeration and medical aerosols. One major challenge expected in the replacement of existing working fluids with HFOs is the solubility and solvation of additives in such hydrophobic and oleophobic low dielectric semifluorinated solvents. The study of the solvation of chemistries that represent those additives by HFOs is, therefore, of great relevance. In this work, we systematically investigate how the polarity and structure of fragments (the tail, t) that represent those additives affect their binding energy (<i>E</i>_b) with HFO-1234ze (1,1,1,3-tetrafluoropropene) (the solvent, s; <i>E</i>_b^st). We also compare and contrast those results with those for the working fluids that are most widely used in the industry, the hydrofluoroalkanes (HFAs) HFA-134a and HFA-227. Three main chemistries were investigated: alkanes, ethers, and esters. It was found that HFO-1234ze interacts quite favorably with ethers and esters, as indicated by their <i>E</i>_b^st, while <i>E</i>_b^st with alkanes was much lower. While ether and ester groups showed little difference in <i>E</i>_b^st, the much lower self-interaction energy between ether tail–tail fragments (<i>E</i>_b^tt) is expected to result in improved solubility/solvation of those groups in HFO-1234ze when compared with the more polar ester groups. The ratio <i>E</i>_b^st/<i>E</i>_b^tt is defined as the enhancement factor (<i>E</i>_enh) and is expected to be a better predictor of solubility/solvation of the tail fragments. The branching of the tail groups upon the addition of pendant CH₃ groups did not significantly affect the solvation by the propellant. At low branching density (one CH₃ pendant group), it did not affect tail–tail self-interaction either. However, at high enough branching (two CH₃ groups), steric hindrance caused a significant decrease in <i>E</i>_b^tt and thus an increase in <i>E</i>_enh, suggesting that branching may be used as a strategy to enhance solvation in HFO propellants. Finally, the solvation behavior of HFO-1234ze was found to be similar to that of HFA-134a, thus suggesting similar considerations may apply for both propellants, when solvation properties are of a concern to the application