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Abstract: The canine corpus luteum (CL) typically sustains elevated plasma progesterone concentrations for 2 months or more, with a peak approximately 15–25 days after ovulation, followed by a slow decline. The processes involved in the slow, protracted regression of the CL over the remaining 1.5–2-month period in nonpregnant bitches and until shortly prepartum in pregnant bitches are not well characterized. The rapid luteolysis that occurs immediately prepartum appears to be a result of a prepartum rise in peripheral PGF. The potential role of PGF in the slow regression process in the several weeks preceding parturition and in nonpregnant bitches after 15–25 days after ovulation is not known. Therefore, plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F2-alpha (PGFM), progesterone (P4) and estradiol (E2) were determined and compared in bitches during nonpregnant diestrus (n =9) or pregnancy (n =8). During the gradual decrease in plasma concentrations of progesterone in both groups, the P4 pattern appeared unrelated to changes in either E2 or PGFM concentrations. The PGFM pattern was different between diestrus and pregnant bitches (P >0.01); there was an apparent progressive but slow increase in PGFM in pregnant bitches from Days 30 to 60, followed by a large increase prior to parturition; concentrations declined immediately postpartum. However, there were no increases in PGFM during the same interval in nonpregnant bitches. Mean estradiol concentrations were sporadically elevated during the last third of pregnancy and less so in nonpregnant diestrus; there was no acute prepartum increase in estradiol associated with the PGFM increase. In summary, although there were no apparent changes in peripheral PGF2α concentration involved in regulating the slow protracted phase of luteal regression in nonpregnant bitches, modest increases in PGFM may play a role in ovarian function after mid-gestation in pregnant bitches. Furthermore, the acute prepartum rise in PGFM was not dependent on any concomitant increase in estradiol concentrations. [Copyright &y& Elsevier]

Abstract: The objective was to evaluate the influence of varying plasma progesterone (P4) concentrations throughout the luteal phase in dairy cows on PGF2α production (assessed as plasma concentrations of 13,14-dihydro-15-keto-PGF2α; PGFM) following treatment with estradiol-17β (E2) or oxytocin (OT). In all experiments, time of ovulations was synchronized with the OvSynch protocol and Day 0 corresponded to day of second GnRH injection. In Experiment 1, non-lactating dairy cows on Day 6 remained non-treated (n =9), received 20mg LH (n =7), or had ovarian follicles larger than 6mm aspirated (n =8). In Experiment 2, cows on Day 6 were untreated (n =9) or received 5000IU hCG (n =10). In Experiments 1 and 2, all cows received 3mg E2 on Day 17, and blood samples were collected every 30min from 2h before to 10h after E2. Experiment 3 was conducted in two periods, each from Days 0 to 17 of the estrous cycle. At the end of Period 1, animals switched treatments in a crossover arrangement. Animals in Group 2/8 (n =4) received 2kg/d of concentrate in the first period and 8kg/d in the second period. Animals in Group 8/2 (n =7) received the alternate sequence. Blood was collected daily for measurement of P4 4h after concentrate feeding. On Day 17, blood was collected from 1h before to 1h after a 100IU OT injection. In Experiment 1, both plasma P4 and release of PGF2α were similar between LH-treated and control cows (P >0.10). In Experiment 2, plasma P4 was elevated to a greater extent on Day 17 in cows treated with hCG (P <0.05) and plasma PGFM was also greater in hCG-treated animals (treatment×time interaction; P <0.05). In Experiment 3, there was a group×period interaction (P <0.01) for plasma P4, indicating that less concentrate feeding was associated with greater plasma P4. Release of PGF2α in response to OT was greater for cows receiving less concentrate (group×period interaction; P <0.05). In conclusion, dairy cows with more elevated blood P4 concentrations released more PGF2α in response to E2 or OT. [Copyright &y& Elsevier]

The widespread use of potent androgen receptor signaling inhibitors (ARSIs) has led to an increasing emergence of AR-independent castration-resistant prostate cancer (CRPC), typically driven by loss of AR expression, lineage plasticity, and transformation to prostate cancers (PCs) that exhibit phenotypes of neuroendocrine or basal-like cells. The anti-apoptotic protein BCL2 is upregulated in neuroendocrine cancers and may be a therapeutic target for this aggressive PC disease subset. There is an unmet clinical need, therefore, to clinically characterize BCL2 expression in metastatic CRPC (mCRPC), determine its association with AR expression, uncover its mechanisms of regulation, and evaluate BCL2 as a therapeutic target and/or biomarker with clinical utility. Here, using multiple PC biopsy cohorts and models, we demonstrate that BCL2 expression is enriched in AR-negative mCRPC, associating with shorter overall survival and resistance to ARSIs. Moreover, high BCL2 expression associates with lineage plasticity features and neuroendocrine marker positivity. We provide evidence that BCL2 expression is regulated by DNA methylation, associated with epithelial-mesenchymal transition, and increased by the neuronal transcription factor ASCL1. Finally, BCL2 inhibition had antitumor activity in some, but not all, BCL2-positive PC models, highlighting the need for combination strategies to enhance tumor cell apoptosis and enrich response.