The delicate interaction between an embryo and the uterus to initiate implantation and maintain pregnancy is one of the most elegant and fascinating interactions in human biology. Understanding the molecular events of embryo-maternal interaction is of interest to reproductive biologists, clinicians and couples affected by infertility. We have established the baboon as the non-human primate model for studying embryo implantation. Infusion of chorionic gonadotropin (CG), the major embryonic signal of primates, into the uterine cavity of normal cycling baboons during the window of receptivity induces a myriad of morphological, biochemical and molecular changes in the estrogen and progesterone primed endometrium. The luminal epithelium responds by forming plaques, the overall secretory function of the glandular epithelium increases and the stromal response is characterized by induction of α-smooth muscle actin (αSMA). Cross talk between ovarian and embryonic hormones is evidenced by the fact that these responses are inhibited upon treatment with a progesterone receptor antagonist. CG signals principally through the seven transmembrane LH/CG G-protein coupled receptor, and activates a mitogen activated protein kinase pathway in the endometrial epithelium that is unique and independent of all the classical signaling pathways. In the stromal compartment, CG both rescues stromal fibroblasts from their apoptotic demise and also differentiates them into the decidualized phenotype. We propose that stromal cell survival and differentiation is mediated by a critical modulator of cell fate, Notch-1. Thus, CG is an important embryonic signal which modulates communication between the embryo and the endometrium and induces changes that are critical to successful implantation.

Nearly 75% of in vitro fertilization (IVF) treatments do not result in live births and patients are largely guided by a generalized agebased prognostic stratification. We sought to provide personalized and validated prognosis by using available clinical and embryo data from prior, failed treatments to predict live birth probabilities in the subsequent treatment. We generated a boosted tree model, IVF BT , by training it with IVF outcomes data from 1,676 first cycles (C1s) from 2003-2006, followed by external validation with 634 cycles from 2007-2008, respectively. We tested whether this model could predict the probability of having a live birth in the subsequent treatment (C2). By using nondeterministic methods to identify prognostic factors and their relative nonredundant contribution, we generated a prediction model, IVF BT , that was superior to the age-based control by providing over 1,000-fold improvement to fit new data (p < 0.05), and increased discrimination by receiver-operative characteristic analysis (area-under-the-curve, 0.80 vs. 0.68 for C1, 0.68 vs. 0.58 for C2). IVF BT provided predictions that were more accurate for ∼83% of C1 and ∼60% of C2 cycles that were out of the range predicted by age. Over half of those patients were reclassified to have higher live birth probabilities. We showed that data from a prior cycle could be used effectively to provide personalized and validated live birth probabilities in a subsequent cycle. Our approach may be replicated and further validated in other IVF clinics.regression tree model | in vitro fertilization prediction | live birth prediction | in vitro fertilization prognostics | personalized medicine

Successful implantation necessitates modulation of the uterine environment by the embryo for a specific period of time during the menstrual cycle. Infusion of chorionic gonadotropin (CG) into the oviducts of baboons to mimic embryo transit induces a myriad of morphological, biochemical, and molecular changes in the endometrium. Endometrial epithelial cells from both baboons and humans when stimulated by CG in vitro, activates a cAMP-independent MAPK pathway leading to prostaglandin E(2) (PGE(2)) synthesis. This study shows that in the human endometrial cell line, HES, CG, acting via its G-protein coupled receptor, phosphorylates protein kinase B, c-Raf, and ERK1/2 in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. Furthermore, ERK1/2 phosphorylation is independent of the signaling paradigms of Galpha(s), Galpha(I), and epidermal growth factor receptor (EGFR) transactivation, typical of gonadal cells, indicating an alternative signaling pattern in the endometrium. After phosphorylation by CG, ERK1/2 translocates to the nucleus in a time-dependent manner. Downstream of ERK1/2, CG activates the nuclear transcription factor, Elk1, also in a PI3K-MAPK-dependent manner. Lastly, we show that in HES cells, this pathway regulates the expression of the microsomal enzyme PGE(2) synthase (mPTGES), a terminal prostanoid synthase responsible for PGE(2) synthesis. CG regulates the mPTGES promoter and also induces mPTGES synthesis in HES cells via the PI3K-ERK1/2 pathway. We suggest that this alternative PI3K-ERK-Elk pathway activated by CG regulates prostaglandin production by the endometrial epithelium and serves as an early trigger to prepare the endometrium for implantation.

IntroductionLeaf extract of Mentha arvensis or mint plant was used as reducing agent for the synthesis of green silver nanoparticles (GSNPs) as a cost-effective, eco-friendly process compared to that of chemical synthesis. The existence of nanoparticles was characterized by ultraviolet–visible spectrophotometry, dynamic light scattering, Fourier transform infrared spectroscopy, X-ray diffraction, energy-dispersive X-ray analysis, atomic-force microscopy and transmission electron microscopy analyses, which ascertained the formation of spherical GSNPs with a size range of 3–9 nm. Anticancer activities against breast cancer cell lines (MCF7 and MDA-MB-231) were studied and compared with those of chemically synthesized (sodium borohydride [NaBH4]-mediated) silver nanoparticles (CSNPs).Materials and methodsCell survival of nanoparticle-treated and untreated cells was studied by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell-cycle analyses were carried out using fluorescence-activated cell sorting. Cell morphology was observed by fluorescence microscopy. Expression patterns of PARP1, P53, P21, Bcl2, Bax and cleaved caspase 9 as well as caspase 3 proteins in treated and untreated MCF7 and MDA-MB-231 cells were studied by Western blot method.ResultsMTT assay results showed that Mentha arvensis-mediated GSNPs exhibited significant cytotoxicity toward breast cancer cells (MCF7 and MDA-MB-231), which were at par with that of CSNPs. Cell cycle analyses of MCF7 cells revealed a significant increase in sub-G1 cell population, indicating cytotoxicity of GSNPs. On the other hand, human peripheral blood lymphocytes showed significantly less cytotoxicity compared with MCF7 and MDA-MB-231 cells when treated with the same dose. Expression patterns of proteins suggested that GSNPs triggered caspase 9-dependent cell death in both cell lines. The Ames test showed that GSNPs were nonmutagenic in nature.ConclusionGSNPs synthesized using Mentha arvensis may be considered as a promising anticancer agent in breast cancer therapy. They are less toxic and nonmutagenic and mediate caspase 9-dependent apoptosis in MCF7 and MDA-MB-231 cells.

The primary embryonic signal in primates is chorionic gonadotropin (CG, designated hCG in humans), that is classically associated with corpus luteum rescue and progesterone production. However, research over the past decade has revealed the presence of the hCG receptor in a variety of extragonadal tissues. Additionally, discoveries of the multiple variants of hCG, namely, native hCG, hyperglycosylated hCG (hyp-hCG) and the β-subunit of the hyperglycosylated hCG (hCG-free β) has established a role for extragonadal actions of hCG. For the initiation and maintenance of pregnancy, hCG mediates multiple placental, uterine and fetal functions. Some of these include development of syncytiotrophoblast cells, mitotic growth and differentiation of the endometrium, localized suppression of the maternal immune system, modulation of uterine morphology and gene expression and coordination of intricate signal transduction between the endometrium. Recurrent pregnancy loss, preeclampsia and endometriosis are associated with altered responses of hCG, all of which have a detrimental effect on pregnancy. A role for hyp-hCG in mediating the development of both trophoblastic and non-trophoblastic tumors has also been suggested. Other significant non-gonadal applications of hCG include predicting preeclampsia, determining the risk of Down’s syndrome and gestational trophoblastic disease, along with relaxing myometrial contractility and preventing recurrent miscarriages. Presence of hCG free-β in serum of cancer patients enables its usage as a diagnostic tumor marker. Thus, the extragonadal functions of hCG encompasses a wide spectrum of applications and is an open area for continued investigation.