Anti-SYP monoclonal antibody, clone 309DU34.5.5

Background: With the advent of secondary androgen receptor (AR)-targeted therapies in metastatic castration resistant prostate cancer (PC), nonadenocarcinoma PCs are becoming more prevalent. Many of these cancers express neuroendocrine markers, which may provide biomarkers for emergence of this disease state. We aimed to quantify the expression of synaptophysin (Syp) on circulating tumor cells (CTCs) from serial samples of patients being treated with abiraterone acetate or enzalutamide. Methods: CTCs were isolated from 44 patients with castration resistant PC before starting abiraterone or enzalutamide, at 4, 8, and 12 weeks on therapy, and at progression. Patients were stratified into 3 groups: de novo resistance, short response, and long response. CTCs were enumerated on the CellSearch platform and Syp expression was quantified using the open fluorescent channel on the platform. Correlative analyses were performed. Results: A baseline CTC count of 5 or greater was associated with a more rapid time to progression and increasing CTC counts correlated with emergence of drug resistance. Syp was readily detectable on the surface of CTCs, and baseline percentage CTC Syp expression was significantly associated with time to progression. Furthermore, in evaluable patients, percent CTC Syp expression increased with the emergence of drug resistance. We also found that prior exposure to AR-targeted therapies was inversely associated with progression free survival. Conclusions: We have demonstrated that Syp can be quantified on CTCs and that Syp expression correlates with resistance to abiraterone and enzalutamide. Larger studies testing Syp as a biomarker of emergence of nonadenocarcinoma disease and as a marker of response to AR-targeted therapies are warranted. (C) 2017 Elsevier Inc. All rights reserved.

Dentate granule cell (DGC) mossy fiber sprouting (MFS) in mesial temporal lobe epilepsy (mTLE) is thought to underlie the creation of aberrant circuitry which promotes the generation or spread of spontaneous seizure activity. Understanding the extent to which populations of DGCs participate in this circuitry could help determine how it develops and potentially identify therapeutic targets for regulating aberrant network activity. In this study, we investigated how DGC birthdate influences participation in MFS and other aspects of axonal plasticity using the rat pilocarpine-induced status epilepticus (SE) model of mTLE. We injected a retrovirus (RV) carrying a synaptophysin-yellow fluorescent protein (syp-YFP) fusion construct to birthdate DGCs and brightly label their axon terminals, and compared DGCs born during the neonatal period with those generated in adulthood. We found that both neonatal and adult-born DGC populations participate, to a similar extent, in SE-induced MFS within the dentate gyrus inner molecular layer (IML). SE did not alter hilar MF bouton density compared to sham-treated controls, but adult-born DGC bouton density was greater in the IML than in the hilus after SE. Interestingly, we also observed MF axonal reorganization in area CA2 in epileptic rats, and these changes arose from DGCs generated both neonatally and in adulthood. These data indicate that both neonatal and adult-generated DGCs contribute to axonal reorganization in the rat pilocarpine mTLE model, and indicate a more complex relationship between DGC age and participation in seizure-related plasticity than was previously thought.