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Objective: Mitogen-activated protein kinases (MAPKs) are involved in the proliferation and survival of endometriotic lesions. Vemurafenib (PLX4032) is a novel protein kinase inhibitor that targets BRAF, a member of the MAPK pathway. The present study tested the in vitro and in vivo effects of PLX4032 on endometriotic cells., Research Design and Methods: We conducted a laboratory study in a tertiary-care university hospital from January 2013 to September 2013. We enrolled a cohort of 40 patients: 20 with histologically proven endometriosis and 20 unaffected women. A thorough surgical examination of the abdominopelvic cavity was performed on all of the study participants. Ex vivo stromal and epithelial cells were extracted from endometrial and endometriotic biopsies from both sets of patients. Proliferation, apoptosis, pERK/ERK ratio, cell cycle regulation (Cyclin D1 and CDK4) and inflammation (PTGS2) were explored with and without PLX4032 treatment. Human endometriotic lesions were implanted into 40 nude mice that were separated into two groups according to PLX4032 or vehicle treatment, which they received for four weeks, before sacrifice and histological examination., Results: Treating endometriotic cells with PLX4032 abrogated the phosphorylation of ERK, significantly reducing the pERK/ERK ratio in both epithelial and stromal cells from endometriotic women compared to the controls (p < 0.05). In addition, treatment with PLX4032 significantly decreased proliferation in both stromal and epithelial cells with a concomitant decrease in Cyclin D1/CDK4 complex and PTGS2 levels. Using a murine model of endometriosis, we observed that PLX4032-treated mice displayed a significant decrease in implant volume compared to the initial size; a slight, but non-significant, increase in size was observed in the vehicle-treated mice., Conclusion: Our data suggest that MAPKs and BRAF are involved in the pathogenesis of endometriosis. PLX4032-induced inhibition of BRAF controlled endometriotic growth, both in vitro and in vivo, and could constitute a promising target for the treatment of endometriosis.

Melatonin is highly produced in the placenta where it protects against molecular damage and cellular dysfunction arising from hypoxia/re-oxygenation-induced oxidative stress as observed in primary cultures of syncytiotrophoblast. However, little is known about melatonin and its receptors in the human placenta throughout pregnancy and their role in villous trophoblast development. The purpose of this study was to determine melatonin-synthesizing enzymes, arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT), and melatonin receptors (MT1 and MT2) expression throughout pregnancy as well as the role of melatonin and its receptors in villous trophoblast syncytialization. Our data show that the melatonin generating system is expressed throughout pregnancy (from week 7 to term) in placental tissues. AANAT and HIOMT show maximal expression at the 3rd trimester of pregnancy. MT1 receptor expression is maximal at the 1st trimester compared to the 2nd and 3rd trimesters, while MT2 receptor expression does not change significantly during pregnancy. Moreover, during primary villous cytotrophoblast syncytialization, MT1 receptor expression increases, while MT2 receptor expression decreases. Treatment of primary villous cytotrophoblast with an increasing concentration of melatonin (10 pM-1 mM) increases the fusion index (syncytium formation; 21% augmentation at 1 mM melatonin vs. vehicle) and β-hCG secretion (121% augmentation at 1 mM melatonin vs. vehicle). This effect of melatonin appears to be mediated via its MT1 and MT2 receptors. In sum, melatonin machinery (synthetizing enzymes and receptors) is expressed in human placenta throughout pregnancy and promotes syncytium formation, suggesting an essential role of this indolamine in placental function and pregnancy well-being., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: To determine the pronostic factors of pregnancy in intra-uterine insemination using sperm of donor (IIU-D) by analysing female factors, data from the ovarian stimulation and even the characteristics of the donor selected for the recipient couple., Material and Methods: Retrospective study between January 2002 and December 2009. It took place at the University and Hospital of Amiens over 149 couples performing a total of 535 IIU-D cycles. Factors related to the pregnancy were defined thanks to uni and multivariate analysis., Results: Female age was 30.6 ± 4.3 years old (6% of the cycles with women>38). The initiated pregnancy rate per cycle was 27.9%; the birth rate per cycle was 20.4% and the cumulative live birth rate over 63.4% for six cycles. In multivariate analysis prognostic factors of success were: day 3 of estradiol level less than 80 pg/mL (P<0.05), no tube defects (P=0.022), cured and benign womb pathology (P=0.005), a higher number of follicles greater than 16 mm the day of the ovulation triggering (P=0.0018) and a higher number of pregnancies already obtained by the donor in ART in the CECOS (P<0.001). Neither the female age nor the donor age was associated with a probability of success., Discussion and Conclusion: Classical pronostic factors concerning the female profile and the ovarian stimulation quality have been found. But the most interesting and original part is that the most significant factor concerns the donor and his history of pregnancy in Assisted Reproductive Technology (ART) in the center. This may be very useful to guide the choice of the donor for the recipients., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Embryo implantation consists of a series of events promoting the invasion of the endometrium and then the uterine arterial system by the extra-embryonic trophoblast. In order for this semi-heterologous implantation to succeed, the endometrium has to first undergo a number of structural and biochemical changes (decidualization). The decidua's various constituents subsequently play a role in the embryonic implantation. The third step is the transformation of the uterine vascular system and the growth of the placenta, which will provide the foetoplacental unit with nutrients. Several physiopathological aspects will be discussed: 1) the implantation window, regulated by maternal and embryonic hormonal secretions and thus influenced by any defects in the latter: dysharmonic luteal phase, 21-hydroxylase block, abnormal integrin expression, 2) the successive trophoblast invasions of uterine vessels which, when defective, lead to early embryo loss or late-onset vascular pathologies, as preeclampsia, 3) the pregnancy's immunological equilibrium, with a spontaneously tolerated semi-allogeneic implant, 4) the impact of pro-coagulant factors (thrombophilia) on the pregnancy's progression, 5) the environment of the uterus, ranging from hydrosalpinx to uterine contractions. In summary, the least anatomical or physiological perturbation can interfere with human embryonic implantation - a very particular phenomenon and a true biological paradox.

A cytologic grading method of fine needle aspiration smears has been applied to 192 cases of breast carcinoma. Grade I defines well differenciated carcinoma, grade II pleioporphic tumor cells, grade III anaplastic carcinoma. Special attention was given to the unfavorable forms of tumors (grade III). The cytologic grading was correlated with the NMT clinical classification, with the notion of acute exacerbation and with axillary nodes involvement. The correlation of grading with the clinical course of the disease was evaluated after a twelve months follow up. In 4% of patients classified in grade I, 8% of grade II and 58% of grade III, metastases, local recurrence or death had occurred within one year. The contribution of grading to the identification of fast growing tumors is discussed.