The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin-dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. © 2017 American Cancer Society.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US and its impact continues to increase in women. Oxidant insults during critical periods of early life appear to increase risk of COPD through-out the life course. To better understand susceptibility to early life exposure to oxidant air pollutants we used Fisher (F344), Sprague-Dawley (SD) and Wistar (WIS) male and female neonatal rat pups to assess: (A) if strain (i.e. genetics), sex, or stage of early life development affected baseline lung antioxidant or redox enzyme levels and (B) if these same factors modulated antioxidant responsiveness to acute ozone exposure (1 ppm × 2 h) on post-natal day (PND) 14, 21, or 28. In air-exposed pups from PND14-28, some parameters were unchanged (e.g. uric acid), some decreased (e.g. superoxide dismutase), while others increased (e.g. glutathione recycling enzymes) especially post-weaning. Lung total glutathione levels decreased in F344 and SD pups, but were relatively unchanged in WIS pups. Post-ozone exposure, data suggest that: (1) the youngest (PND14) pups were the most adversely affected; (2) neonatal SD and WIS pups, especially females, were more prone to ozone effects than males of the same age and (3) F344 neonates (females and males) were less susceptible to oxidative lung insult, not unlike F344 adults. Differences in antioxidant levels and responsiveness between sexes and strains and at different periods of development may provide a basis for assessing later life health outcomes - with implications for humans with analogous genetic or dietary-based lung antioxidant deficits.

Vesamicol (AH5183) inhibits the uptake of acetylcholine into cholinergic neuronal storage vesicles. Earlier in vitro studies have demonstrated that such inhibition can lead to a failure of transmission, particularly in peripheral cholinergic tissues. The present study was designed to determine whether vesamicol could inhibit central cholinergic transmission in conscious freely moving rats. Central (lateral cerebroventricular) injection of 20 micrograms of vesamicol significantly reduced the hypertensive and bradycardic response to subsequent central injection of physostigmine in spontaneously hypertensive rats. Inhibition of the pressor response was greatest when physostigmine was administered 1 hr after vesamicol. Acetylcholine and choline levels were determined in three brain regions derived from rats treated one hr earlier with either vehicle or vesamicol. Acetylcholine levels were found to be unaltered after vesamicol treatment, although choline levels were significantly higher in two brain regions. These results are consistent with the ability of vesamicol to inhibit the function of central cholinergic cardiovascular regulatory neurons. The mechanism for this inhibition is not related to depletion of total brain acetylcholine content but may be due to depletion of a small critical pool of transmitter.

Epidemiologic studies of air pollution effects on respiratory health report significant modification by sex. Studies of children suggest stronger effects among boys in early life and girls in later childhood. In adults, particularly the elderly, studies report stronger effects among women. Differential inflammatory or antioxidant responses are purported. Herein we examined sex or maturation influences in prepubertal Wistar rats [a strain prone to ozone (O3)‐induced lung injury/inflammation] on (A) lung antioxidant and related enzyme levels and (B) antioxidant response to O3. Female (F) and male (M) 14, 21, and 28 d (pre‐, at, post‐weaning) pups were exposed to air, 0.5 or 1 ppm O3 x 2h. In air controls, no sex‐based differences in lung antioxidant levels were observed. From 14‐28 d, weight increased (F: 1.7‐2.7‐fold; M: 1.7‐3.1‐fold); with M>F at 28 d. Likewise, lung uric acid increased (1.1‐1.2‐fold), as did ascorbic acid (1.4‐2.7‐fold), glutathione (GSH) peroxidase (1.0‐3.5‐fold), GSH transferase (1.0‐2.9‐fold), GSH reductase (1.2‐4.2‐fold), and G‐6‐PDH (10‐fold) (per gwet wt). Conversely, SOD declined 30‐42%. Lung GSH was relatively stable. At 0h, 1 ppm O3‐exposed F 14 d pups had decreased GSH and related enzyme activity. At 21 d, exposure was without effect on GSH; and males showed O3‐induced increases in uric acid. At 28 d, no antioxidant changes were apparent. Together, data suggest health risk due to early life pollutant exposure is greatest in very immature females. With maturity, especially post‐weaning, rat lung antioxidant reserve increases, thus reducing susceptibility to pollutant‐induced oxidative stress. (Abstract does not reflect USEPA policy)