ABSTRACT
Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.
Subject(s)
Consensus , Glioma , Mutation , Proto-Oncogene Proteins B-raf , Adolescent , Child , Female , Humans , Male , Young Adult , Brain Neoplasms/genetics , Brain Neoplasms/drug therapy , Canada , Glioma/genetics , Glioma/drug therapy , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/geneticsABSTRACT
We report on the rearrangement chemistry of model phosphorylated peptides during collision-induced dissociation (CID), where intramolecular phosphate group transfers are observed from donor to acceptor residues. Such "scrambling" could result in inaccurate modification localization, potentially leading to misidentifications. Systematic studies presented herein provide mechanistic insights for the unusually high phosphate group rearrangements presented some time ago by Reid and coworkers (Proteomics 2013, 13 [6], 964-973). It is postulated here that a basic residue like histidine can play a key role in mediating the phosphate group transfer by deprotonating the serine acceptor site. The proposed mechanism is consistent with the observation that fast collisional activation by collision-cell CID and higher-energy collisional dissociation (HCD) can shut down rearrangement chemistry. Additionally, the rearrangement chemistry is highly dependent on the charge state of the peptide, mirroring previous studies that less rearrangement is observed under mobile proton conditions.
Subject(s)
Organophosphates/chemistry , Phosphopeptides/chemistry , Binding Sites , Histidine/chemistry , Mass Spectrometry , Peptide Fragments/chemistry , Phosphorylation , Protein Binding , Protons , Serine/chemistryABSTRACT
Vibrational ion spectroscopy techniques coupled with mass spectrometry are applied to standard metabolites as a proof-of-principle demonstration for the structural identification of unknown metabolites. The traditional room temperature infrared multiple photon dissociation (IRMPD) spectroscopy technique is shown to differentiate chemical moieties in isobaric and isomeric variants. These results are compared to infrared spectra of cryogenically cooled analyte ions, showing enhanced spectral resolution, and thus also improved differentiation between closely related molecules, such as isomers. The cryogenic spectroscopy is effected in a recently developed mass-selective cryogenic linear ion trap, which is capable of high sensitivity and the ability to measure the IR spectra of multiple analytes simultaneously.