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Item Cyclical Hematochezia in a 30-Year-Old Female Linked to Endometriosis(2021-06-10) Lugo, Adrian; Martyn, Colin; Cho, Isaac S.; Fraser, Scott; Gislason, GardarClinical manifestations of gastrointestinal (GI) dysfunction are diverse. However, many of these symptoms such as abdominal pain and hematochezia are nonspecific and can be caused by a variety of ailments. As such, it is imperative to develop a broad differential diagnosis including conditions outside of the GI system. In this case report, we demonstrate how endometriosis was inadvertently discovered as the culprit in a patient with abdominal pain and hematochezia. A 30-year-old female with a history of endometriosis, total laparoscopic hysterectomy with left salpingo-oophorectomy, and right salpingectomy presented to the clinic with abdominal pain. It was gradual in onset, occurred 3 to 4 days monthly, and was associated with diarrhea, tenesmus, and mild hematochezia with clots. Alleviating factors included defecation and warmth. No weight loss was noted. Physical exam was significant for right lower quardrant and subprapubic tenderness. A colonoscopy was performed which demonstrated an infiltrative, submucosal, non-bleeding 3 cm mass in the proximal rectum. The terminal ileum and colon were unremarkable. An endoscopic ultrasound with biopsy via fine need aspiration of the mass was then performed. The biopsy demonstrated glands within smooth muscle bundles positive for cytokeratin 7, Ber-EP4, weak to moderate staining of the estrogen receptor, and very weak focal positivity for PAX-8, all of which was most consistent with endometriosis. The patient was subsequently referred to a surgeon for removal of the affected rectum, but she ultimately declined surgery. Her symptoms were mildly controlled with oral contraceptives, but the hematochezia persisted during her menstrual cycles. Patients often present with vague GI symptoms that are manifestations of non-GI processes. This case report demonstrates how an extra-intestinal condition was able to infiltrate through the intestinal wall to cause abdominal pain and hematochezia. We believe the patient’s symptoms stemmed from her endometriosis as she has an intact right ovary and the hematochezia was cyclical in nature. Other investigations have reported multiple segments of the bowel being affected by endometriosis, but the literature is scarce in the standardization of treatment for these cases. This report highlights the importance of potentially resecting bowel segments that are affected by endometriosis as these lesions may cause significant morbidity if the underlying condition is not treated accordingly.Item Distinct molecular pathways in ovarian endometrioid adenocarcinoma with concurrent endometriosis(Wiley, 2018) Zhang, Chi; Wang, Xiyin; Anaya, Yanett; Parodi, Luca; Cheng, Lijun; Anderson, Matthew L.; Hawkins, Shannon M.; Medicine, School of MedicineWomen with endometriosis, a benign growth of endometrial tissue outside the uterine cavity, are at increased risk of specific histotypes of epithelial ovarian cancer, such as ovarian endometrioid adenocarcinoma (OEA). Women with OEA who have endometriosis at time of surgical staging demonstrate improved clinical prognosis compared to women with OEA without evidence of endometriosis. However, the molecular contributions of the endometriotic tumor microenvironment to these ovarian cancers remain poorly understood. As a starting point, we used a platform for genome‐wide transcriptomic profiling to compare specimens of OEA from women with and without concurrent endometriosis and benign reproductive tract tissues, including proliferative endometrium and typical and atypical endometrioma samples (n = 20). Principle component analysis revealed distinct clustering between benign and malignant samples as well as malignant samples with and without concurrent endometriosis. Examination of gene signatures revealed that OEA with concurrent endometriosis contained a unique molecular signature compared to OEA without concurrent endometriosis, distinguished by 682 unique genes differentially expressed (fold change < or >1.5, p < 0.01). Bioinformatic analysis of these differentially expressed gene products using ingenuity pathway analysis revealed activation of NFkB signaling, an inflammatory signaling pathway constitutively active in endometriosis. DAVID functional annotation clustering further revealed enrichment in RAS signaling as both cytoskeleton organization and GTPase regulator activity relied heavily on RAS protein signal transduction. Gene set enrichment analysis highlighted immune and inflammatory nodes involved in OEA with concurrent endometriosis. These observations provide novel resources for understanding molecular subtleties potentially involved in OEA within the context of the endometriotic tumor microenvironment.Item Three-Dimensional Biofabrication Models of Endometriosis and the Endometriotic Microenvironment(MDPI, 2020-11) Wendel, Jillian R. H.; Wang, Xiyin; Smith, Lester J.; Hawkins, Shannon M.; Obstetrics and Gynecology, School of MedicineEndometriosis occurs when endometrial-like tissue grows outside the uterine cavity, leading to pelvic pain, infertility, and increased risk of ovarian cancer. The present study describes the optimization and characterization of cellular spheroids as building blocks for Kenzan scaffold-free method biofabrication and proof-of-concept models of endometriosis and the endometriotic microenvironment. The spheroid building blocks must be of a specific diameter (~500 μm), compact, round, and smooth to withstand Kenzan biofabrication. Under optimized spheroid conditions for biofabrication, the endometriotic epithelial-like cell line, 12Z, expressed high levels of estrogen-related genes and secreted high amounts of endometriotic inflammatory factors that were independent of TNFα stimulation. Heterotypic spheroids, composed of 12Z and T-HESC, an immortalized endometrial stromal cell line, self-assembled into a biologically relevant pattern, consisting of epithelial cells on the outside of the spheroids and stromal cells in the core. 12Z spheroids were biofabricated into large three-dimensional constructs alone, with HEYA8 spheroids, or as heterotypic spheroids with T-HESC. These three-dimensional biofabricated constructs containing multiple monotypic or heterotypic spheroids represent the first scaffold-free biofabricated in vitro models of endometriosis and the endometriotic microenvironment. These efficient and innovative models will allow us to study the complex interactions of multiple cell types within a biologically relevant microenvironment.Item Transcriptomic analyses of ovarian clear-cell carcinoma with concurrent endometriosis(Frontiers, 2023-08-08) Collins, Kaitlyn E.; Wang, Xiyin; Klymenko, Yuliya; Davis, Noah B.; Martinez, Maria C.; Zhang, Chi; So, Kaman; Buechlein, Aaron; Rusch, Douglas B.; Creighton, Chad J.; Hawkins, Shannon M.; Obstetrics and Gynecology, School of MedicineIntroduction: Endometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC). Methods: To explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing. Results: Analysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)]. Discussion: These studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.