Search

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3 and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including β-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions' growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure. [ABSTRACT FROM AUTHOR]

Laparoscopy has advanced over the last three decades with residency training programs focusing on trans-abdominal laparoscopic techniques whether conventional or robotic. Despite attempts over many years to adopt vaginal surgery as the preferred method of hysterectomy, traditional vaginal surgery has largely fallen out of favor. Vaginal natural orifice transluminal endoscopic surgery (vNOTES) has gained popularity with patients and promises to provide an attractive option, but the surgical skills of many gynecologists have limited its widespread adoption. We explore the use of robot-assisted vNOTES (RA-vNOTES), which offers improved ergonomics, visualization, and wristed instruments for more precise surgery. Robotic vNOTES, was originally performed in Taiwan by Dr. Chyi-Long Lee in 2014.1 Our center has used the robotic vaginal approach for hysterectomy, myomectomy, sacrocolpopexy, adnexal surgery, endometriosis excision, and more. We have also shown feasibility in performing surgery on patients with a completely obliterated posterior cul-de-sac, long been thought to be a contraindication for the transvaginal approach. Enhancements have been made to improve safety and efficiency, such as the use of indocyanine green to visualize the ureters. There are some limitations on instrument maneuverability and reach with the current da Vinci® Xi (Intuitive Surgical, Sunnyvale, California) platform. However, with over 300 cases logged in our center, these limitations may be overcome with the new da Vinci® SP (Intuitive Surgical, Sunnyvale, California). We are eager to share our experience and hope that more gynecologic surgeons will choose this innovative approach for the benefit of our patients.

EPH receptors (EPHs), the largest family of tyrosine kinases, phosphorylate downstream substrates upon binding of ephrin cell surface-associated ligands. In a large cohort of endometriotic lesions from individuals with endometriosis, we found that EPHA2 and EPHA4 expressions are increased in endometriotic lesions relative to normal eutopic endometrium. Because signaling through EPHs is associated with increased cell migration and invasion, we hypothesized that chemical inhibition of EPHA2/4 could have therapeutic value. We screened DNA-encoded chemical libraries (DECL) to rapidly identify EPHA2/4 kinase inhibitors. Hit compound, CDD-2693, exhibited picomolar/nanomolar kinase activity against EPHA2 (K i : 4.0 nM) and EPHA4 (K i : 0.81 nM). Kinome profiling revealed that CDD-2693 bound to most EPH family and SRC family kinases. Using NanoBRET target engagement assays, CDD-2693 had nanomolar activity versus EPHA2 (IC 50 : 461 nM) and EPHA4 (IC 50 : 40 nM) but was a micromolar inhibitor of SRC, YES, and FGR. Chemical optimization produced CDD-3167, having picomolar biochemical activity toward EPHA2 (K i : 0.13 nM) and EPHA4 (K i : 0.38 nM) with excellent cell-based potency EPHA2 (IC 50 : 8.0 nM) and EPHA4 (IC 50 : 2.3 nM). Moreover, CDD-3167 maintained superior off-target cellular selectivity. In 12Z endometriotic epithelial cells, CDD-2693 and CDD-3167 significantly decreased EFNA5 (ligand) induced phosphorylation of EPHA2/4, decreased 12Z cell viability, and decreased IL-1β-mediated expression of prostaglandin synthase 2 ( PTGS2 ). CDD-2693 and CDD-3167 decreased expansion of primary endometrial epithelial organoids from patients with endometriosis and decreased Ewing's sarcoma viability. Thus, using DECL, we identified potent pan-EPH inhibitors that show specificity and activity in cellular models of endometriosis and cancer., Competing Interests: Competing interests statement:The authors declare no competing interest.