Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Particular solutions of generalized Euler-Poisson-Darboux equation

In this article we consider the generalized Euler-Poisson-Darboux equation $${u}_{tt}+\frac{2\gamma }{t}{{u}_{t}}={u}_{xx}+{u}_{yy} +\frac{2\alpha }{x}{{u}_{x}}+\frac{2\beta }{y}{{u}_y},\quad x>0,\;y>0,\;t>0.$$ We construct particular solutions in an explicit form expressed by the Lauricella hypergeometric function of three variables. Properties of each constructed solutions have been investigated in sections of surfaces of the characteristic cone. Precisely, we prove that found solutions have singularity $1/r$ at $r\to 0$, where ${{r}^2}={{( x-{{x}_0})}^2}+{{( y-{{y}_0})}^2}-{{( t-{{t}_0})}^2}$

Quantitation of total and free teriflunomide (A77 1726) in human plasma by LC-MS/MS

The clinical activity of leflunomide, a drug used in the treatment of rheumatoid arthritis, is due to its active metabolite, teriflunomide. In vitro studies indicate that at least 99% of teriflunomide is expected to be protein bound in human plasma in vivo, leaving<1% in the unbound or 'free' state for clinical activity. To examine details of the relationships between leflunomide dosing and patient response, it is necessary to have an assay that is sufficiently sensitive to measure the minor fraction of free teriflunomide in patient samples. Therefore, we aimed to develop and validate an LC-MS/MS method for the measurement of teriflunomide, and use it to determine the total and free teriflunomide concentration in patients with rheumatoid arthritis. Teriflunomide and its deuterated internal standard were extracted from human plasma and separated using a reversed phase method with a C18 column. Detection was conducted with an API 3000 LC-MS/MS System by monitoring selected ions in negative ion MRM. Optimal detection occurred at m/z 269.1/160.0 (teriflunomide) and m/z 273.1/164.0 (teriflunomide-D4). Over a linear range of 5-500 μg/L, the inter-batch precision ranged from 1.9 to 8.8% and accuracy from -8.4 to 8.0%. The intra- and inter-batch assay precision for quality control samples ranged from 2.1-5.4% and 5.7-7.1% respectively. The procedure was applied to assess total and free plasma concentrations of teriflunomide in patients with rheumatoid arthritis. Free teriflunomide was approximately 0.11% of total teriflunomide, and there was a significant correlation (r2=0.724) between free and total teriflunomide concentrations. A validated, accurate and sensitive method was developed and successfully applied for the measurement of total and free teriflunomide concentration in human plasma samples. This method has been shown to be reproducible and sensitive and can be applied to clinical samples.Halima Rakhila, Tomas Rozek, Ashley Hopkins, Susanna Proudman, Les Cleland, Michael James, Michael Wies