Whole-genome and transcriptome analysis enhances precision cancer treatment options.

BACKGROUND: Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data provided by whole-genome and transcriptome sequencing and analysis (WGTA) present an opportunity to align a much larger proportion of patients to therapies. PATIENTS AND METHODS: Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected. RESULTS: Clinically actionable targets were identified for 83% of patients, of which 37% of patients received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, poly-ADP ribose polymerase inhibitors and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%) and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies. CONCLUSIONS: Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.

A microprocessor system for the digital synthesis of pulsed and continuous discharges of electric fish (or animal vocalizations).

Traditionally, the sensitivity of electric fish to electric stimuli has been investigated using a variety of electronically generated signal functions, for example sine, square, and sawtooth waves (both continuous and pulsed). None of these resemble the species- or sex-specific electric organ discharges (EODs) of fish. Therefore, EODs recorded on magnetic tape were used in open-loop playback experiments. However, as shown in the present paper, the waveforms of EODs reproduced from magnetic tape are distorted, and cannot be manipulated with speed and accuracy as to frequency or pulse repetition rate by feedback from the experiment. Good EOD imitations are generated by our microprocessor-based system for the digital synthesis of EODs which is controlled by a small 'personal computer'. Digitized EOD samples edited by computer are output by the fast digital-to-analogue converter of the microprocessor system. This system was devised for the synthesis of pulse-type (discontinuous) and wave type (continuous) EODs with continuous, on-line frequency and amplitude control. The rate of digital synthesis is 500 kHz in pulse-type EODs, and 250-500 kHz in wave type EODs at 0.06-0.24 Hz frequency resolution, depending on the repetition frequency of the synthesized wave EOD. The present paper describes the steps in EOD synthesis, and indicates some applications which benefit from the playback of high-fidelity imitations of natural EODs at amplitudes and frequencies selected by the experimenter, or automatically controlled by feedback from the experiment in closed-loop applications.