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Study Question: Is it possible to establish a genetically engineered mouse model (GEMM) of endometriosis that mimics the natural spread of invasive endometrium?Summary Answer: Endometriosis occurs in an ARID1A (AT-rich interactive domain-containing protein 1A) and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutant GEMM of endometrial dysfunction following salpingectomy.What Is Known Already: Although mouse models of endometriosis have long been established, most models rely on intraperitoneal injection of uterine fragments, steroid hormone treatments or the use of immune-compromised mice.Study Design, Size, Duration: Mice harboring the lactotransferrin-Cre (LtfCre0/+), Arid1afl, (Gt)R26Pik3ca*H1047R and (Gt)R26mTmG alleles were subject to unilateral salpingectomies at 6 weeks of age. Control (n = 9), LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/+ (n = 8) and LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/fl (n = 9) were used for the study. The (Gt)R26mTmG allele was used for the purpose of fluorescent lineage tracing of endometrial epithelium. LtfCre0/+; (Gt)R26mTmG (n = 3) and LtfCre0/+; (Gt)R26Pik3ca*H1047R/mTmG; Arid1afl/fl (n = 4) were used for this purpose. Mice were followed until the endpoint of vaginal bleeding at an average time of 17 weeks of age.Participants/materials, Setting, Methods: At 6 weeks of age, mice were subjected to salpingectomy surgery. Mice were followed until the time point of vaginal bleeding (average 17 weeks), or aged for 1 year in the case of control mice. At time of sacrifice, endometriotic lesions, ovaries and uterus were collected for the purpose of histochemical and immunohistochemical analyses. Samples were analyzed for markers of the endometriotic tissue and other relevant biomarkers.Main Results and the Role Of Chance: Following salpingectomy, LtfCre0/+; (Gt)R26Pik3ca*H1047R/mTmG; Arid1afl/fl mice developed endometriotic lesions, including lesions on the ovary, omentum and abdominal wall. Epithelial glands within lesions were negative for ARID1A and positive for phospho-S6 staining, indicating ARID1A-PIK3CA co-mutation status, and expressed EGFP (enhanced green fluorescent protein), indicating endometrial origins.Large-scale Data: N/A.Limitations, Reasons For Caution: LtfCre0/+; (Gt)R26Pik3ca*H1047R; Arid1afl/fl mice develop vaginal bleeding as a result of endometrial dysfunction at an average age of 17 weeks and must be sacrificed. Furthermore, while this model mimics the natural spread of endometriotic tissue directly from the uterus to the peritoneum, the data presented do not reject current hypotheses on endometriosis pathogenesis.Wider Implications Of the Findings: The idea that endometriosis is the result of abnormal endometrial tissue colonizing the peritoneum via retrograde menstruation has gained widespread support over the past century. However, most models of endometriosis take for granted this possibility, relying on the surgical removal of bulk uterine tissue and subsequent transplantation into the peritoneum. Growing evidence suggests that somatic mutations in ARID1A and PIK3CA are present in the endometrial epithelium. The establishment of a GEMM which mimics the natural spread of endometrium and subsequent lesion formation supports the hypothesis that endometriosis is derived from mutant endometrial epithelium with invasive properties.Study Funding/competing Interest(s): This research was supported by the American Cancer Society PF-17-163-02-DDC (M.R.W.), the Mary Kay Foundation 026-16 (R.L.C.) and the Ovarian Cancer Research Fund Alliance 457446 (R.L.C.). The authors declare no competing interests. [ABSTRACT FROM AUTHOR]

Philaenus spumarius is a widespread insect species in the Holarctic region. Here, by focusing on the mtDNA gene COI but also using the COII and Cyt b genes and the nuclear gene EF-1α, we tried to explain how and when its current biogeographic pattern evolved by providing time estimates of the main demographic and evolutionary events and investigating its colonization patterns in and out of Eurasia. Evidence of recent divergence and expansion events at less than 0.5 Ma ago indicate that climate fluctuations in the Mid-Late Pleistocene were important in shaping the current phylogeographic pattern of the species. Data support a first split and differentiation of P. spumarius into two main mitochondrial lineages: the “western”, in the Mediterranean region and the “eastern”, in Anatolia/Caucasus. It also supports a following differentiation of the “western” lineage into two sub-lineages: the “western-Mediterranean”, in Iberia and the “eastern-Mediterranean” in the Balkans. The recent pattern seems to result from postglacial range expansion from Iberia and Caucasus/Anatolia, thus not following one of the four common paradigms. Unexpected patterns of recent gene-flow events between Mediterranean peninsulas, a close relationship between Iberia and North Africa, as well as high levels of genetic diversity being maintained in northern Europe were found. The mitochondrial pattern does not exactly match to the nuclear pattern suggesting that the current biogeographic pattern of P. spumarius may be the result of both secondary admixture and incomplete lineage sorting. The hypothesis of recent colonization of North America from both western and northern Europe is corroborated by our data and probably resulted from accidental human translocations. A probable British origin for the populations of the Azores and New Zealand was revealed, however, for the Azores the distribution of populations in high altitude native forests is somewhat puzzling and may imply a natural colonization of the archipelago. [ABSTRACT FROM AUTHOR]

Dexamethasone (Dex), co-administered to lung adenocarcinoma patients with pemetrexed chemotherapy, protects against pemetrexed cytotoxicity by inducing reversible G1 arrest, reflected by the effect of Dex on FLT-PET images of patient tumors. However, perioperative Dex treatment increases survival but the mechanism is unknown. In cells with glucocorticoid receptor-α (GR) expression corresponding to higher clinical tumor levels, Dex-induced growth arrest was followed by marked cell expansion, beta-galactosidase expression and Ki67 negativity, despite variable p53 and K-RAS status. Dex induced a transient early surge in p21Cip1. However, a progressive, irreversible loss of clonogenic growth, whose time of onset was dependent on GR level and Dex dose, was independent of p21Cip1and caused by gradual accumulation of p27Kip1 due to transcriptional activation of p27Kip1 by Dex. This effect was independent of canonical pathways of senescence or p27Kip1 regulation. The in vitro observations were reflected by growth suppression and P27Kip1 induction in GR-overexpressing tumor xenografts compared with isogenic low-GR tumors. Extended Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27Kip1 gene in GR overexpressing lung tumor cell populations and hence could improve outcome of surgery/pemetrexed chemotherapy and sensitize tumors to immunotherapy. [ABSTRACT FROM AUTHOR]