Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

DNAzymes targeting c-Jun may have therapeutic potential as inhibitors of tumor angiogenesis and growth.

Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ~4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 ( P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years. Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

An experimental model of focal segmental glomerular sclerosis (FSGS) was developed in rats by the combined administration of puromycin-aminonucleoside (AMNS) and protamine sulfate (PS). Male Sprague-Dawley rats, uninephrectomized three weeks before, received daily injections of subcutaneous AMNS (1 mg/100 g body wt) and intravenous PS (2 separated doses of 2.5 mg/100 g body wt) for four days. The series of injections were repeated another three times at 10 day intervals. The animals were sacrificed on days 24, 52, and 80. They developed nephrotic syndrome and finally renal failure. The time-course curve of creatinine clearance dropped and showed significant difference (P less than 0.01) from that of each control group, such as, AMNS alone, PS alone or saline injected. Their glomeruli showed changes of progressive FSGS. The ultrastructural studies in the initial stage revealed significant lack of particles of perfused ruthenium red on the lamina rara externa and marked changes in epithelial cell cytoplasm. Therefore, it is suggested that the administration of PS enhances the toxicity of AMNS on the glomerulus and readily produces progressive FSGS in rats resulting in the end-stage renal disease.

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Chronic administration of intravenous adriamycin (1 mg . kg-1 twice weekly for 8 weeks) to rabbits resulted in a cardiomyopathy which was similar to that occurring in patients with adriamycin cardiotoxicity. We studied systemic and renal haemodynamics and the activation of vasoconstrictor mechanisms reflected by changes in plasma renin activity (PRA), noradrenaline (NA) and vasopressin (AVP) levels during the development of heart failure in this animal model. By 8 weeks cardiac failure was clearly established. At postmortem all animals had dilated hearts, pleural and pericardial effusions, ascites and hepatic congestion. Heart weights were increased (8.1 +/- 0.7 g in treated animals n = 9 vs 6.0 +/- 0.2 g in controls n = 9 p less than 0.05). Cardiac output (measured by thermodilution) fell at 8 weeks from 799 +/- 61 ml . min-1 to 624 +/- 44 ml . min-1 (n = 6 p less than 0.05) with a parallel fall in mean blood pressure from 85 +/- 2 mmHg to 75 +/- 4 mmHg. Total peripheral resistance rose in four of the six rabbits. Renal blood flow fell from 108 +/- 4 ml . min-1 to 61 +/- 6 ml . min-1 (p less than 0.05) by 8 weeks. Renal vascular resistance increased in all animals. PRA increased from 5.1 +/- 0.5 ng AI . ml-1 . h-1 to 11.6 +/- 2.6 ng AI . ml-1 . h-1 by 4 weeks (p less than 0.05) and remained elevated thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)

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To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to controls (n = 39), rats with infarction (n = 16) had markedly elevated plasma immunoreactive atrial natriuretic peptide concentrations (1205.8 +/- 180.9 vs. 126.7 +/- 8.9 pg/ml, p less than 0.001) and reduced immunoreactive atrial natriuretic peptide concentrations in right and left atria (31.4 +/- 4.6 vs. 61.2 +/- 3.2 ng/mg, p less than 0.001; 14.9 +/- 2.2 vs. 32.7 +/- 2.4 ng/mg, p less than 0.001, respectively). Right ventricular weight increased in proportion to infarct size, and both were correlated with plasma immunoreactive atrial natriuretic peptide levels (r = 0.825, p less than 0.001 and r = 0.816, p less than 0.001, respectively). Right atrial immunoreactive atrial natriuretic peptide content was significantly higher than left in both controls and rats with infarction. Both right and left atrial immunoreactive atrial natriuretic peptide concentrations were negatively correlated with both right ventricular weight as well as plasma immunoreactive atrial natriuretic peptide concentrations (right atrium: r = -0.816, p less than 0.001, r = -0.708, p less than 0.01; left atrium: r = -0.687, p less than 0.01, r = -0.644, p less than 0.01, respectively). These results suggest that chronic stimulation of atrial natriuretic peptide release from both atria is associated with increased turnover and depleted stores of atrial natriuretic peptide in atria in proportion to the severity of heart failure. It also suggests that plasma atrial natriuretic peptide levels may be used as a reliable index of cardiac decompensation in chronic heart failure.