This study supports the hypothesis that a handheld fan directed to the face reduces the sensation of breathlessness. The fan was acceptable to participants: it is inexpensive, portable, enhances self-efficacy, and available internationally. It should be recommended as part of a palliative management strategy for reducing breathlessness associated with advanced disease.

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

Data AvailabilitySequencing data that support the findings of this paper have been deposited in the European Genome-phenome Archive with the accession code EGAD00001005434. Code AvailabilityAll code required to reproduce the analysis outline in this manuscript can be found in the main and supplementary methods. There are no restrictions to the accessibility of this code. Author ContributionsAN designed and implemented the rapid autopsy study, collected the samples, performed the experiments, analyzed data and wrote the manuscript. MG and S.D.P contributed expertise in pathology and sample collection for the rapid autopsy study. ID-B and NG assisted in study implementation, and along with JC, assisted with sample collection at autopsy. M.S performed the structural variant analysis. M.D.E performed genomic data generation and QC. LB conducted data management. XL, PL-S and JW were involved with autopsy sample collection, advice on experiments and data analysis, and XL contributed to experiments, paper writing, and figure design. LA and IM assisted with data analysis. NG assisted with study Implementation. SMac coordinated the sequencing of samples from the OCCAMS project and contributed to paper writing. SM and AM provided pathology data. TT, SG, LP and DG assisted in implementation and ethical conduct of the autopsy study. R.H.H and AH were involved in surgical sample collection and providing surgical expertise. M.R.S contributed to critical evaluation of the study data and manuscript. D.C.W was responsible for data analysis, paper writing, and assuring integrity of data. The OCCAMS consortium was the vehicle through which the infrastructure and funding was obtained to support the study and the consortium contributed to discussions on the ICGC data and the clinical ramifications. R.C.F provided grant funding and was responsible for study design, supervision of the project, writing the paper and assuring integrity of the data.

Feasibility work is essential, even for simple widely employed interventions.