Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Background GD2 and GD3 are the tumor-associated glycolipid antigens found in a broad spectrum of human cancers. GD2-specific antibody is currently a standard of care for high risk neuroblastoma therapy. In this study, the pattern of GD2 and GD3 expression among pediatric/AYA (adolescent or young adult) tumors was determined, providing companion diagnostics for targeted therapy. Methods Ninety-two specimens of human osteosarcoma (OS), rhabdomyosarcoma (RMS), Ewing family of tumors (EFT), desmoplastic small round cell tumor (DSRCT) and melanoma were analyzed for GD2/GD3 expression by immunohistochemistry. Murine monoclonal antibody 3F8 was used for GD2 staining, and R24 for GD3. Staining was scored according to both intensity and percentage of positive tumor cells from 0 to 4. Results Both gangliosides were highly prevalent in OS and melanoma. Among other tumors, GD3 expression was higher than GD2 expression. Most OS samples demonstrated strong staining for GD2 and GD3, whereas expression for other tumors was highly variable. Mean intensity of GD2 expression was significantly more heterogeneous (p<0.001) when compared with GD3 across tumor types. When assessing the difference between GD2 and GD3 expression in all tumor types combined, GD3 expression had a significantly higher score (p=0.049). When analyzed within each cancer, GD3 expression was significantly higher only in DSRCT (p=0.002). There was no statistical difference in either GD2 or GD3 expression between primary and recurrent sarcomas. Conclusion GD2/GD3 expression among pediatric solid tumors is common, albeit with variable level of expression. Especially for sarcoma patients, these gangliosides can be potential targets for antibody based therapies.

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Background: Advances in biotechnology have raised expectations that biomarkers, including genetic profiles, will yield information to accurately predict outcomes for individuals. However, results to date have been disappointing. In addition, statistical methods to quantify the predictive information in markers have not been standardized.Methods: We discuss statistical techniques to summarize predictive information, including risk distribution curves and measures derived from them, that relate to decision making. Attributes of these measures are contrasted with alternatives such as receiver operating characteristic curves, R