Probes for PRL

Cocaine use disorder (CUD) is associated with prefrontal cortex dysfunction and cognitive deficits that may contribute to persistent relapse susceptibility. As the relationship between cognitive deficits, cortical abnormalities and drug seeking is poorly understood, development of relevant animal models is of high clinical importance. Here, we used an animal model to characterize working memory and reversal learning in rats with a history of extended access cocaine self-administration and prolonged abstinence. We also investigated immediate and long-term functional changes within the prelimbic cortex (PrL) in relation to cognitive performance and drug-seeking. Adult male rats underwent 6 days of short-access (1 h/day) followed by 12 days of long-access (6 h/day) cocaine self-administration, or received passive saline infusions. Next, rats were tested in delayed match-to-sample (DMS) and (non)match-to-sample (NMS) tasks, and finally in a single context + cue relapse test on day 90 of abstinence. We found that a history of chronic cocaine self-administration impaired working memory, though sparing reversal learning, and that the components of these cognitive measures correlated with later drug-seeking. Further, we found that dysregulated metabolic activity and mGlu5 receptor signaling in the PrL of cocaine rats correlated with past working memory performance and/or drug-seeking, as indicated by the analysis of cytochrome oxidase reactivity, mGlu5 and Homer 1b/c protein expression, as well as Arc mRNA expression in mGlu5-positive cells. These findings advocate for a persistent post-cocaine PrL dysfunction, rooted in ineffective compensatory changes and manifested as impaired working memory performance and hyperreactivity to cocaine cues. Considering the possible interplay between the neural correlates underlying post-cocaine cognitive deficits and drug-seeking, cognitive function should be evaluated and considered when developing neurobiologically-based treatments of cocaine relapse.

During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.

The Prolactin Receptor (PRLR) is a type 1 cytokine receptor that is expressed in a subset of breast cancers and may contribute to its pathogenesis. It is relatively over-expressed in ~25% of human breast tumors while expressed at low levels in some normal human tissues including the mammary gland. We developed an anti-PRLR antibody-drug conjugate (ADC), to target PRLR positive breast cancer. REGN2878-DM1 is comprised of a fully human high affinity function-blocking anti-PRLR IgG1 antibody (REGN2878) conjugated via a non-cleavable SMCC linker to the cytotoxic maytansine derivative DM1. Both unconjugated REGN2878 and conjugated REGN2878-DM1 block PRL mediated activation in vitro and are rapidly internalized into lysosomes. REGN2878-DM1 induces potent cell cycle arrest and cytotoxicity in PRLR-expressing tumor cell lines. In vivo, REGN2878-DM1 demonstrated significant antigen-specific anti-tumor activity against breast cancer xenograft models. In addition, REGN2878-DM1 showed additive activity when combined with the anti-estrogen agent fulvestrant. These results illustrate promising anti-tumor activity against PRLR positive breast cancer xenografts and support the evaluation of anti-PRLR ADCs as potential therapeutic agents in breast cancer.