Aberrant uterine folding in mice disrupts implantation chamber formation and alignment of embryo-uterine axes.

The uterine luminal epithelium folds characteristically in mammals, including humans, horses and rodents. Improper uterine folding in horses results in pregnancy failure, but the precise function of folds remains unknown. Here, we uncover dynamic changes in the 3D uterine folding pattern during early pregnancy with the entire lumen forming pre-implantation transverse folds along the mesometrial-antimesometrial axis. Using a time course, we show that transverse folds are formed before embryo spacing, whereas implantation chambers form as the embryo begins attachment. Thus, folds and chambers are two distinct structures. Transverse folds resolve to form a flat implantation region, after which an embryo arrives at its center to attach and form the post-implantation chamber. Our data also suggest that the implantation chamber facilitates embryo rotation and its alignment along the uterine mesometrial-antimesometrial axis. Using WNT5A- and RBPJ-deficient mice that display aberrant folds, we show that embryos trapped in longitudinal folds display misalignment of the embryo-uterine axes, abnormal chamber formation and defective post-implantation morphogenesis. These mouse models with disrupted uterine folding provide an opportunity to understand uterine structure-based mechanisms that are crucial for implantation and pregnancy success. This article has an associated 'The people behind the papers' interview.

Early growth response 1 transcription factor is essential for the pathogenic properties of human endometriotic epithelial cells.

Although a non-malignant gynecological disorder, endometriosis displays some pathogenic features of malignancy, such as cell proliferation, migration, invasion and adaptation to hypoxia. Current treatments of endometriosis include pharmacotherapy and/or surgery, which are of limited efficacy and often associated with adverse side effects. Therefore, to develop more effective therapies to treat this disease, a broader understanding of the underlying molecular mechanisms that underpin endometriosis needs to be attained. Using immortalized human endometriotic epithelial and stromal cell lines, we demonstrate that the early growth response 1 (EGR1) transcription factor is essential for cell proliferation, migration and invasion, which represent some of the pathogenic properties of endometriotic cells. Genome-wide transcriptomics identified an EGR1-dependent transcriptome in human endometriotic epithelial cells that potentially encodes a diverse spectrum of proteins that are known to be involved in tissue pathologies. To underscore the utility of this transcriptomic data set, we demonstrate that carbonic anhydrase 9 (CA9), a homeostatic regulator of intracellular pH, is not only a molecular target of EGR1 but is also important for maintaining many of the cellular properties of human endometriotic epithelial cells that are also ascribed to EGR1. Considering therapeutic intervention strategies are actively being developed for EGR1 and CAIX in the treatment of other pathologies, we believe EGR1 and its transcriptome (which includes CA9) will offer not only a new conceptual framework to advance our understanding of endometriosis but will also furnish new molecular vulnerabilities to be leveraged as potential therapeutic options in the future treatment of endometriosis.

Evaluation of corneal topography, pachymetry and higher order aberrations for detecting subclinical keratoconus.

PURPOSE: To compare corneal topography, pachymetry and higher order aberrations in keratoconic and normal eyes; to investigate their association in keratoconic eyes; and to determine their diagnostic ability for detecting subclinical keratoconus in a Nepalese population. METHODS: Ninety-six eyes of 48 keratoconus patients and 50 normal eyes of 50 control subjects were included in this study. The eyes of keratoconus patients were classified into four different study groups: subclinical, stage 1, stage 2 and advanced stage keratoconus. In each eye, corneal topography, pachymetry and corneal aberrometry indices were measured using a Sirius corneal tomographer. The study parameters of keratoconic eyes were compared with normal eyes, and the possible association of corneal aberrometry with topography and pachymetry indices was investigated. The area under curve (AUC) of receiver operating characteristic (ROC) curves along with optimal cutoff values with best sensitivity and specificity were also determined for each index to detect subclinical keratoconus. RESULTS: All the indices except average keratometry measurements (Kavg and mmavg ) and spherical aberration (SA) were found to be significantly different in subclinical keratoconus compared to the control group (p < 0.05). In keratoconic eyes, all corneal aberrations were significantly correlated with the topography and pachymetry indices (range of ρ: -0.25 to 0.96; all p < 0.05) except for trefoil and minimum corneal thickness (Thkmin ). All the indices except Kavg , mmavg and SA showed excellent diagnostic ability (AUC > 0.90) in detecting subclinical keratoconus. The cutoff values proposed for the asymmetry index of the corneal back surface (SIb ), Strehl ratio of point spread function (PSF), coma and Baiocchi-Calossi-Versaci index of corneal back surface (BCVb ) each showed excellent sensitivity (100%) and specificity (≥97%). CONCLUSIONS: Corneal higher order aberrations were found to be significantly elevated in subclinical keratoconus compared to healthy controls. SIb , PSF, coma and BCVb were identified as the most powerful Sirius indices for the detection of subclinical keratoconus.

Genetic and epigenetic changes in the eutopic endometrium of women with endometriosis: association with decreased endometrial αvß3 integrin expression.

About 40% of women with infertility and 70% of women with pelvic pain suffer from endometriosis. The pregnancy rate in women undergoing IVF with low endometrial integrin αvß3 (LEI) expression is significantly lower compared to the women with high endometrial integrin αvß3 (HEI). Mid-secretory eutopic endometrial biopsies were obtained from healthy controls (C; n=3), and women with HEI (n=4) and LEI (n=4) and endometriosis. Changes in gene expression were assessed using human gene arrays and DNA methylation data were derived using 385 K Two-Array Promoter Arrays. Transcriptional analysis revealed that LEI and C groups clustered separately with 396 differentially expressed genes (DEGs) (P<0.01: 275 up and 121 down) demonstrating that transcriptional and epigenetic changes are distinct in the LEI eutopic endometrium compared to the C and HEI group. In contrast, HEI vs C and HEI vs LEI comparisons only identified 83 and 45 DEGs, respectively. The methylation promoter array identified 1304 differentially methylated regions in the LEI vs C comparison. The overlap of gene and methylation array data identified 14 epigenetically dysregulated genes and quantitative RT-PCR analysis validated the transcriptomic findings. The analysis also revealed that aryl hydrocarbon receptor (AHR) was hypomethylated and significantly overexpressed in LEI samples compared to C. Further analysis validated that AHR transcript and protein expression are significantly (P<0.05) increased in LEI women compared to C. The increase in AHR, together with the altered methylation status of the 14 additional genes, may provide a diagnostic tool to identify the subset of women who have endometriosis-associated infertility.

Psycho-social impact of visual impairment on health-related quality of life among nursing home residents.

BACKGROUND: Visual impairment (VI) affects physical, psychological, and emotional well-being, and social life as well. The purpose of this exploratory study was to assess the psycho-social impact of VI on health-related quality of life (HRQoL) among nursing home residents. METHODS: This cross-sectional study involved 272 residents of 60 years or older residing in seven nursing homes of the Kathmandu Valley, Nepal. Comprehensive ocular examinations, including near and distance vision assessment and refractions were carried out. VI was defined as visual acuity (VA) less than 6/18 in the better eye. Residents were divided into two groups: one group did not have VI (in whom VA was greater than or equal to 6/18 in the better eye), and the other had VI (in whom VA was worse than 6/18 in the better eye).Face-to-face interviews were conducted filling out a 36-item The Medical Outcomes Study Short-Form (SF-36) questionnaire. The SF-36 questionnaire was scored according to the scoring algorithm SF-36 subscales. RESULTS: The mean age of residents was 74.68 ± 8.19 years (range, 60-99 years) and the majority were female (78.68%). The mean composite score of SF-36 was 46.98 ± 13.08. VI detrimentally affected scores of both the physical and the mental components, but the impact of VI was slightly greater for the physical component than that for the mental component. There was a trend towards a lower composite score as well as each subscale score of the SF-36 in participants with VI than in those without VI. CONCLUSION: VI has a negative effect on HRQoL. HRQoL is reduced among nursing home residents and the reduction in the HRQoL bears a positive association with VI.

Comparison between novel zipper device and conventional methods for skin closure: a systematic review and meta-analysis.

Introduction: The zipper device is a wound closure device that can be directly applied over the intact skin on either side of the wound edges and does not need anchoring into the skin or subcutaneous plane. The noninvasive nature of the zipper device makes it less time-consuming and less painful, but its effectiveness and related complications need to be studied. Methods: Prospective registration of the protocol followed in this study was done. Electronic databases were searched for relevant articles, and their screening was completed, followed by data extraction and analysis. The odds ratio, mean difference, or standardised mean difference were used as an effect measure per the nature of the variables. Surgical site infection, wound dehiscence, skin closure time, scar score, and patient satisfaction were compared in this study. Results: A total of 10 studies were identified, out of which eight compared zippers with sutures and two compared zippers with stapler devices. Compared to the suture, the zipper device took 4.9 min less to close the incision, and the scar scale outcome reported after one month was inferior, while other results were not significant. Staples showed a lower patient satisfaction level and no difference in complications. Conclusion: The zipper device is a less technically demanding and less time-consuming method of skin closure, with no significant difference in the complication rate compared to conventional methods. The zipper device is an effective measure to use in settings with less expertise or at health institutions after assessing the cost at the local level.

Yes Associated Transcriptional Regulator 1 (YAP1) and WW Domain Containing Transcription Regulator (WWTR1) are required for murine pregnancy initiation.

Endometrial stromal cell decidualization is required for pregnancy success. Although this process is integral to fertility, many of the intricate molecular mechanisms contributing to decidualization remain undefined. One pathway that has been implicated in endometrial stromal cell decidualization in humans in vitro is the Hippo signaling pathway. Two previously conducted studies showed that the effectors of the Hippo signaling pathway, YAP1 and WWTR1, were required for decidualization of primary stromal cells in culture. To investigate the in vivo role of YAP1 and WWTR1 in decidualization and pregnancy initiation, we generated a Progesterone Cre mediated partial double knockout (pdKO) of Yap1 and Wwtr1. Female pdKOs exhibited subfertility, a compromised decidualization response, partial interruption in embryo transport, blunted endometrial receptivity, delayed implantation and subsequent embryonic development, and a unique transcriptional profile. Bulk mRNA sequencing revealed aberrant maternal remodeling evidenced by significant alterations in extracellular matrix proteins at 7.5 days post-coitus in pdKO dams and enrichment for terms associated with fertility-compromising diseases like pre-eclampsia and endometriosis. Our results indicate a required role for YAP1 and WWTR1 for successful mammalian uterine function and pregnancy success.

Ocular morbidity among the children of squatter settlements in Kathmandu.

PURPOSE: To determine the prevalence of ocular morbidity and refractive error among the children of the squatter settlements in Kathmandu. METHODS: A cross-sectional study was carried out at five squatter settlement areas at Kathmandu, including 366 children younger than 16 years. Detailed eye examination included the visual acuity testing, cycloplegic refraction, binocular vision assessment, anterior segment examination, and posterior segment examination. Variations in age, sex, and ethnic distribution of the study population were analyzed through analysis of variance. Pearson χ test with Yate correction was used to analyze different types of ocular morbidity. Pearson correlation coefficient test was performed to correlate refractive error in the right eye and the left eye. RESULTS: Majority of children (28.9%) belonged to the age group 8 to 10 years, and most of them belonged to the Manohara settlement area (40.2%). Male-female ratio was 0.7. Uncorrected and best-corrected visual acuity of better than or equal to 6/9 in at least one eye was found in 87.9% and 99.0% children, respectively. Total ocular morbidity was observed in 33.7%. The common type of ocular morbidity was conjunctivitis (11.2%), refractive error (9.0%), and blepharitis (5.4%). Ocular morbidity was common in infants (57.9%; p = 0.043; odds ratio, 2.8) and 14- to 15-year-old children (52.8%; p = 0.002; odds ratio, 2.5). CONCLUSIONS: Ocular infection and refractive error represent the common ocular morbidity in children living in squatter settlements.

Diaphragmatic rupture secondary to trauma from falling sacks: A case report.

Key Clinical Message: Diaphragmatic hernia does not only occur during high velocity impact or penetrating injury, but also can occur when heavy loads impact the torso. Diaphragmatic hernia must be ruled out in a patient with polytrauma with a chest X-ray at the least. Abstract: Trauma-induced diaphragmatic hernia is a protrusion of abdominal contents through the defect in diaphragm and is an uncommon and less heard of injury. This case report conveys that diaphragmatic hernia should be ruled out in any polytrauma case presenting with shortness of breath with the chest X-ray at the least.

Agreement between Lea Symbols and Patti Pics visual acuity in children and adults.

BACKGROUND: Patti Pics (PP) and Lea Symbols (LS) are commonly used by eye care practitioners worldwide. Although the relationship between the two tests is fairly well understood, the availability of different chart designs (single optotypes, multiple optotypes, multiple optotypes with crowding box) merits futher understanding. The purpose of this study is to explore the agreement between the acuity measures obtained with Patti Pics and Lea Symbols in children and adults and compare their performance with the Sloan Letter (SL) chart in adults. METHODS: Monocular visual acuity was obtained from ninety-three 3 to 5-year-old children using Patti Pics and Lea Symbols. Acuities were also obtained from 113 adults using the same tests under identical conditions. Acuity results obtained with the pediatric tests were compared with the gold-standard Sloan Letter chart in adults. The Bland-Altman method was implemented to compare the level of agreement between tests. RESULTS: Patti Pics yielded worse visual acuity than the Lea Symbols by approximately half a logMAR line in both children (mean difference: -0.07 ± 0.07 logMAR, p <0.01) and adults (Mean difference: -0.05 ± 0.06 logMAR, p <0.01). The 95% limits of agreement between Lea Symbol acuity and Patti pics acuity in children was ± 0.14 logMAR. Mean difference between the Sloan Letter chart and Lea Symbols acuity was not statistically significant (p = 0.08) in adults but the difference was statistically significant between PP and SL (p<0.001). The 95% limits of agreement between LS and SL and between PP and SL was ± 0.19 logMAR and ± 0.22 logMAR, respectively. CONCLUSION: Patti Pics consistently underestimated visual acuity as compared to Lea Symbols both in children and adults although the differences were not clinically significant. The LS and PP did not yield clinically significant differences in acuities when compared with Sloan letters in adults.

Spheroids as a model for endometriotic lesions.

The development and progression of endometriotic lesions are poorly understood, but immune cell dysfunction and inflammation are closely associated with the pathophysiology of endometriosis. There is a need for 3D in vitro models to permit the study of interactions between cell types and the microenvironment. To address this, we developed endometriotic spheroids (ES) to explore the role of epithelial-stromal interactions and model peritoneal invasion associated with lesion development. Using a nonadherent microwell culture system, spheroids were generated with immortalized endometriotic epithelial cells (12Z) combined with endometriotic stromal (iEc-ESC) or uterine stromal (iHUF) cell lines. Transcriptomic analysis found 4,522 differentially expressed genes in ES compared with spheroids containing uterine stromal cells. The top increased gene sets were inflammation-related pathways, and an overlap with baboon endometriotic lesions was highly significant. Finally, to mimic invasion of endometrial tissue into the peritoneum, a model was developed with human peritoneal mesothelial cells in an extracellular matrix. Invasion was increased in the presence of estradiol or pro-inflammatory macrophages and suppressed by a progestin. Taken together, our results strongly support the concept that ES are an appropriate model for dissecting mechanisms that contribute to endometriotic lesion development.

Case of giant appendicolith: A common ailment with a rare finding.

Giant appendicoliths are rare appendicoliths with the largest diameter of more than 2 cm. It can increase the risk of complications such as perforation or abscess formation. This is a case of an uncommon definitive pathology diagnosed for a right iliac fossa calcification with a rare transoperative finding.

MicroRNA-210-3p Regulates Endometriotic Lesion Development by Targeting IGFBP3 in Baboons and Women with Endometriosis.

MicroRNAs (miRs) play an important role in the pathophysiology of endometriosis; however, the role of miR-210 in endometriosis remains unclear. This study explores the role of miR-210 and its targets, IGFBP3 and COL8A1, in ectopic lesion growth and development. Matched eutopic (EuE) and ectopic (EcE) endometrial samples were obtained for analysis from baboons and women with endometriosis. Immortalized human ectopic endometriotic epithelial cells (12Z cells) were utilized for functional assays. Endometriosis was experimentally induced in female baboons (n = 5). Human matched endometrial and endometriotic tissues were obtained from women (n = 9, 18-45 years old) with regular menstrual cycles. Quantitative reverse transcript polymerase chain reaction (RT-qPCR) analysis was performed for in vivo characterization of miR-210, IGFBP3, and COL8A1. In situ hybridization and immunohistochemical analysis were performed for cell-specific localization. Immortalized endometriotic epithelial cell lines (12Z) were utilized for in vitro functional assays. MiR-210 expression was decreased in EcE, while IGFBP3 and COL8A1 expression was increased in EcE. MiR-210 was expressed in the glandular epithelium of EuE but attenuated in those of EcE. IGFBP3 and COL8A1 were expressed in the glandular epithelium of EuE and were increased compared to EcE. MiR-210 overexpression in 12Z cells suppressed IGFBP3 expression and attenuated cell proliferation and migration. MiR-210 repression and subsequent unopposed IGFBP3 expression may contribute to endometriotic lesion development by increasing cell proliferation and migration.

Visual status and ocular morbidity in older adults living in residential care.

BACKGROUND: The frequency of visual impairment and blindness increases with age and is more prevalent among older adults living in residential care centers. The main aim of this study was to assess the visual status and determine the prevalence and major causes of visual impairment and blindness among the older adults living in residential care centers of Kathmandu Valley, Nepal. METHODS: A cross-sectional study was conducted on 385 residents of 60 years or older residing in seven residential care centers of Kathmandu Valley. Presenting distance visual acuity was assessed in each eye with a Snellen chart at 6-m distance in non-standardized outdoor illumination. Objective and subjective refractions were performed and the best-corrected distance visual acuity was considered in the better eye. Near acuity was assessed binocularly with The Lighthouse Near Acuity Card. Complete anterior and posterior segment examination was carried out. RESULTS: The mean age of residents was 74.34 ± 8.19 years. The majority was female residents (78.2 %). The prevalence of visual impairment and blindness was 43.70 %. Adequate refractive correction could alone reduce the prevalence of visual impairment and blindness by 15.40 %. Cataract was the leading cause of visual impairment and blindness, which was followed by age-related macular degeneration, corneal opacity, glaucoma, and macular scar. CONCLUSIONS: The prevalence of visual impairment and blindness is significant among the older adults living in residential care centers. The frequency of visual impairment and blindness can be prevented by adequate refractive correction, frequent eye examination, and appropriate high use of cataract surgery.

SWI/SNF Antagonism of PRC2 Mediates Estrogen-Induced Progesterone Receptor Expression.

Endometrial cancer (EC) is characterized by high estrogen levels unopposed by progesterone. Treatment with progestins is standard for early EC, but the response to progestins is dependent on progesterone receptor (PGR) expression. Here, we show that the expression of PGR in endometrial epithelial cells is dependent on ARID1A, a DNA-binding subunit of the SWI/SNF chromatin-remodeling complex that is commonly mutated in EC. In endometrial epithelial cells with estrogen receptor overexpression, we find that ARID1A promotes estrogen signaling and regulates common gene expression programs. Normally, endometrial epithelial cells expressing estrogen receptors respond to estrogen by upregulating the PGR. However, when ARID1A expression is lost, upregulation of PGR expression is significantly reduced. This phenomenon can also occur following the loss of the SWI/SNF subunit BRG1, suggesting a role for ARID1A- and BRG1-containing complexes in PGR regulation. We find that PGR is regulated by a bivalent promoter, which harbors both H3K4me3 and H3K27me3 histone tail modifications. H3K27me3 is deposited by EZH2, and inhibition of EZH2 in the context of ARID1A loss results in restoration of estrogen-induced PGR expression. Our results suggest a role for ARID1A deficiency in the loss of PGR in late-stage EC and a therapeutic utility for EZH2 inhibitors in this disease.

Interleukin-6 (IL-6) Activates the NOTCH1 Signaling Pathway Through E-Proteins in Endometriotic Lesions.

CONTEXT: NOTCH signaling is activated in endometriotic lesions, but the exact mechanisms remains unclear. IL-6, which is increased in the peritoneal fluid of women with endometriosis, induces NOTCH1 through E-proteins including E2A and HEB in cancer. OBJECTIVE: To study the role of E-proteins in inducing NOTCH1 expression under the regulation of IL-6 in endometriosis. SETTING AND DESIGN: The expression of E-proteins and NOTCH1 was first investigated in endometrium of women with endometriosis and the baboon model of endometriosis. Regulation of E-proteins and NOTCH1 expression was examined after IL-6 stimulation and siRNA mediated inhibition of E2A or/and HEB in human endometriotic epithelial cells (12Z) in vitro, and subsequently following IL-6 treatment in the mouse model of endometriosis in vivo. RESULTS: E2A, HEB, and NOTCH1 were significantly upregulated in glandular epithelium (GE) of ectopic endometrium compared to eutopic endometrium in both women and the baboon model. IL-6 treatment upregulated the expression of NOTCH1 together with E2A and HEB in 12Z cells. Small interfering RNA inhibition of E2A and HEB or HEB alone decreased NOTCH1 expression. Binding efficiency of both E2A and HEB was significantly higher at the binding sites on the human NOTCH1 promoter after IL-6 treatment. Finally, IL-6 treatment resulted in a significantly increased number of endometriotic lesions along with increased expression of E2A, HEB, and NOTCH1 in GE of the lesions compared with the vehicle group in an endometriosis mouse model. CONCLUSIONS: IL-6 induced NOTCH1 expression is mediated by E-proteins in the ectopic GE cells, which may promote endometriotic lesion development.

Establishment of an Immortalized Endometriotic Stromal Cell Line from Human Ovarian Endometrioma.

Endometrial-like stromal cells, one of the main components of endometriotic lesions, are an important in vitro model for studying cellular and molecular mechanisms associated with lesion development in endometriosis. However, the short life span of primary endometriotic stromal cells (Ec-ESCs) limits their use. Human telomerase reverse transcriptase (hTERT) plasmids can be used to develop immortalized cell lines. Here we aimed to establish an endometriotic stromal cell line by hTERT immortalization. Primary Ec-ESCs were obtained from a human ovarian endometriotic cyst. The purity was assessed by morphology and the expression of vimentin, cytokeratin, and human interferon-inducible transmembrane protein 1 (hIFITM1). Cells were infected with hTERT lentiviral vector and selected with hygromycin. hTERT mRNA levels were confirmed by RT-qPCR. Immortalized Ec-ESCs (iEc-ESCs) were characterized by examining the expression of morphological markers and key genes of interest, TP53, estrogen receptor ß (ERß), progesterone receptor (PR), and steroidogenic factor-1 (SF-1). Karyotyping and in vitro decidualization studies were also performed. Ec-ESCs were positive for vimentin and hIFITM1 and negative for cytokeratin, indicating that they were representative of Ec-ESC. The fibroblast-like morphology, expression of TP53, ERß, PR, and SF-1 did not change before and after hTERT immortalization. iEc-ESCs showed an impaired decidualization response like primary Ec-ESCs when compared to normal eutopic stromal cells. Karyotyping showed that 15/19 cells had normal female karyotype, while 4/19 cells had partial trisomy 11q. Collectively, we successfully established and characterized an immortalized endometriotic stromal cell line. It is potentially useful as an in vitro experimental model to investigate endometriosis biology.

A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo.

In many repeat diseases, such as Huntington's disease (HD), ongoing repeat expansions in affected tissues contribute to disease onset, progression and severity. Inducing contractions of expanded repeats by exogenous agents is not yet possible. Traditional approaches would target proteins driving repeat mutations. Here we report a compound, naphthyridine-azaquinolone (NA), that specifically binds slipped-CAG DNA intermediates of expansion mutations, a previously unsuspected target. NA efficiently induces repeat contractions in HD patient cells as well as en masse contractions in medium spiny neurons of HD mouse striatum. Contractions are specific for the expanded allele, independently of DNA replication, require transcription across the coding CTG strand and arise by blocking repair of CAG slip-outs. NA-induced contractions depend on active expansions driven by MutSß. NA injections in HD mouse striatum reduce mutant HTT protein aggregates, a biomarker of HD pathogenesis and severity. Repeat-structure-specific DNA ligands are a novel avenue to contract expanded repeats.

ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion.

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue.