Digital ECMT Cancer Trial Matching Tool: an Open Source Research Application to Support Oncologists in the Identification of Precision Medicine Clinical Trials.

PURPOSE: Matching patients with cancer to precision medicine clinical trials on the basis of their tumor genotype has the potential to improve outcomes for patients who have exhausted standard-of-care treatment options. However, the matching process presents a substantial challenge because of the number of clinical trials available. We describe a free, open source research tool designed to extract relevant trial information to support oncologists in the matching process, and we illustrate its utility with recent case studies of patients who were matched to trials using this tool. METHODS: Trial records are sourced from ClinicalTrials.gov and indexed using natural language processing techniques, including named entity recognition, term normalization, and relationship extraction. Relationships between trials and genetic alterations are assigned scores on the basis of a rule-based system. All data are updated daily. A user interface is provided via R Shiny app. RESULTS: An instance of the trial match tool, configured for UK clinical trials, is hosted by the digital Experimental Cancer Medicine Team (see link in Data Sharing Statement). Users select the relevant cancer type and genetic alteration(s). Matching studies are ranked according to the score assigned for the selected genetic alterations. Results may be downloaded and attached to the patient's health record if desired. The tool is currently being used to support the ongoing TARGET National study, which aims to match up to 6,000 patients to early phase clinical trials. We present three case studies that exemplify relationships between genetic alterations and studies. CONCLUSION: With increasing numbers of precision medicine treatments and as comprehensive molecular profiling of tumor samples becomes more common, decision support tools are likely to become increasingly important. This work represents an important step toward the development and wider implementation of such systems.

An approach to interprofessional management of complex patients: a case report.

INTRODUCTION: Complex patients are frequently high-users of health care resources. Case management has been demonstrated to be an effective and efficient approach for this demographic. CASE PRESENTATION: A 36-year old, medically complex male patient was referred to an interprofessional primary care team to optimize health status. Team involvement included a case manager, nurse practitioner, pharmacist, social worker, team assistant and chiropractor. Interventions involved medication management, smoking cessation, mindfulness skills and musculoskeletal treatment. SUMMARY: Complex patients are increasingly managed by teams. To continue, these teams will have to demonstrate positive outcomes and cost-effectiveness. Chiropractors have skills that can enhance team-based patient care.

INTRODUCTION: Les patients ayant des besoins complexes sont souvent ceux qui utilisent le plus les ressources en soins de santé. La gestion de cas s'est avérée être une approche efficace et efficiente pour ce groupe de personnes. PRÉSENTATION DE CAS: Un patient de 36 ans présentant des problèmes de santé complexes a été dirigé vers une équipe interprofessionnelle de soins primaires afin d'optimiser son état de santé. L'équipe comprenait un gestionnaire de cas, un infirmier praticien, un pharmacien, un travailleur social, un assistant d'équipe et un chiropraticien. Les interventions portaient sur la gestion des médicaments, l'abandon du tabac, les compétences liées à la pleine conscience et le traitement musculosquelettique. RÉSUMÉ: Les patients ayant des besoins complexes sont de plus en plus pris en charge par des équipes. Pour continuer à exercer, ces équipes devront démontrer des résultats positifs et un bon rapport coût-efficacité. Les chiropraticiens ont des compétences qui peuvent améliorer les soins aux patients dispensés en équipe.

Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study.

Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.

Is magnetic topology important for heating the solar atmosphere?

Magnetic fields permeate the entire solar atmosphere weaving an extremely complex pattern on both local and global scales. In order to understand the nature of this tangled web of magnetic fields, its magnetic skeleton, which forms the boundaries between topologically distinct flux domains, may be determined. The magnetic skeleton consists of null points, separatrix surfaces, spines and separators. The skeleton is often used to clearly visualize key elements of the magnetic configuration, but parts of the skeleton are also locations where currents and waves may collect and dissipate. In this review, the nature of the magnetic skeleton on both global and local scales, over solar cycle time scales, is explained. The behaviour of wave pulses in the vicinity of both nulls and separators is discussed and so too is the formation of current layers and reconnection at the same features. Each of these processes leads to heating of the solar atmosphere, but collectively do they provide enough heat, spread over a wide enough area, to explain the energy losses throughout the solar atmosphere? Here, we consider this question for the three different solar regions: active regions, open-field regions and the quiet Sun. We find that the heating of active regions and open-field regions is highly unlikely to be due to reconnection or wave dissipation at topological features, but it is possible that these may play a role in the heating of the quiet Sun. In active regions, the absence of a complex topology may play an important role in allowing large energies to build up and then, subsequently, be explosively released in the form of a solar flare. Additionally, knowledge of the intricate boundaries of open-field regions (which the magnetic skeleton provides) could be very important in determining the main acceleration mechanism(s) of the solar wind.

Copper-induced trafficking of the cU-ATPases: a key mechanism for copper homeostasis.

The Menkes protein (MNK) and Wilson protein (WND) are transmembrane, CPX-type Cu-ATPases with six metal binding sites (MBSs) in the N-terminal region containing the motif GMXCXXC. In cells cultured in low copper concentration MNK and WND localize to the transGolgi network but in high copper relocalize either to the plasma membrane (MNK) or a vesicular compartment (WND). In this paper we investigate the role of the MBSs in Cu-transport and trafficking. The copper transport activity of MBS mutants of MNK was determined by their ability to complement a strain of Saccharomyces cerevisiae deficient in CCC2 (delta ccc2), the yeast MNK/WND homologue. Mutants (CXXC to SXXS) of MBS1, MBS6, and MBSs1-3 were able to complement delta ccc2 while mutants of MBS4-6, MBS5-6 and all six MBS inactivated the protein. Each of the inactive mutants also failed to display Cu-induced trafficking suggesting a correlation between trafficking and transport activity. A similar correlation was found with mutants of MNK in which various MBSs were deleted, but two constructs with deletion of MBS5-6 were unable to traffic despite retaining 25% of copper transport activity. Chimeras in which the N-terminal MBSs of MNK were replaced with the corresponding MBSs of WND were used to investigate the region of the molecules that is responsible for the difference in Cu-trafficking of MNK and WND. The chimera which included the complete WND N-terminus localized to a vesicular compartment, similar to WND in elevated copper. Deletions of various MBSs of the WND N-terminus in the chimera indicate that a targeting signal in the region of MBS6 directs either WND/MNK or WND to a vesicular compartment of the cell.

Butane and propane oxidation by engineered cytochrome P450cam.

The haem monooxygenase cytochrome P450cam has been engineered to oxidise the gaseous alkanes butane and propane to butan-2-ol and propan-2-ol, respectively, by the use of bulky amino acid substitutions to reduce the volume of the substrate pocket and thus improve the enzyme-substrate fit: the F87W/Y96F/T101L/V247L mutant oxidizes butane with a turnover rate of 750 min-1 and 95% yield based on NADH consumed while the wild-type enzyme has an activity of 0.4 min-1 with 4% yield.