The DNA damage response in advanced ovarian cancer: functional analysis combined with machine learning identifies signatures that correlate with chemotherapy sensitivity and patient outcome.

BACKGROUND: Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants. METHODS: We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods. RESULTS: DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS. CONCLUSIONS: Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.

Auditory hemodynamic studies of newborn infants using near-infrared spectroscopic imaging.

The noninvasive study of tissue blood volume and oxygenation using near-infrared light is a new and actively developing technology. We have used near-infrared spectroscopic imaging (NIRSI) to study hemodynamic responses on the auditory cortices evoked by auditory stimulation. Ten healthy newborn infants were studied. The otoacoustic emission hearing test was performed for each infant. Pulse oximetry was used to monitor the heart rate during the measurement, video recording was used to monitor motion artifacts, and the eye movements were noted in order to determine sleep stage. A 16-channel frequency-domain optical imaging system developed in our laboratory was used for NIRSI measurements. The stimuli were presented in trains of seven 1 kHz beeps with 700-ms inter-stimulus intervals. The stimulus trains were separated by 25-s silent periods in order to allow for the hemodynamic delay. In 3/8 cases, we obtained a clear bilateral increase in [HbO/sub 2/], and in two additional cases, a clear response on one hemisphere. The mean change in [HbO/sub 2/] was +0.9+/-0.9muM and the mean change in [Hb] was -0.3+/-0.4muM for those channels producing the largest response for each subject. No statistically significant response was found in 3/8 cases.