Obstetrics and Gynecology Commons^™

P2y2 Purinergic Receptor Gene Deletion Protects Mice From Bacterial Endotoxin And Sepsis-Associated Liver Injury And Mortality, Athis R Arunachalam, Sanju S Samuel, Arunmani Mani, Janielle P Maynard, Kelsey M Stayer, Eric Dybbro, Subapradha Narayanan, Aalekhya Biswas, Saliha Pathan, Krishnakant Soni, Abu Hena Mostafa Kamal, Chandra Shekar R Ambati, Nagireddy Putluri, Moreshwar S Desai, Sundararajah Thevananther

Faculty, Staff and Students Publications

Prostate cancer (PCa) remains a leading cause of mortality among American men, with metastatic and recurrent disease posing significant therapeutic challenges due to a limited comprehension of the underlying biological processes governing disease initiation, dormancy, and progression. The conventional use of PCa cell lines has proven inadequate in elucidating the intricate molecular mechanisms driving PCa carcinogenesis, hindering the development of effective treatments. To address this gap, patient-derived primary cell cultures have been developed and play a pivotal role in unraveling the pathophysiological intricacies unique to PCa in each individual, offering valuable insights for translational research. This review explores the applications …

Oral Follicle-Stimulating Hormone Receptor Agonist Affects Granulosa Cells Differently Than Recombinant Human Fsh, Joie Z Guner, Diana Monsivais, Henry Yu, Fabio Stossi, Hannah L Johnson, William E Gibbons, Martin M Matzuk, Stephen Palmer

Faculty, Staff and Students Publications

Objective:

To determine whether TOP5300, a novel oral follicle stimulating hormone receptor (FSHR) allosteric agonist, elicits a different cellular response than recombinant human FSH (rh-FSH) in human granulosa cells from in vitro fertilization patients.

Design:

Basic science research with a preclinical allosteric FSHR agonist.

Subjects:

Infertility patients at a single academic fertility clinic were recruited under an IRB-approved protocol. Primary granulosa cell cultures were established for 41 patients, of which 8 had normal ovarian reserve (NOR), 17 were of advanced reproductive age (ARA), 12 had a diagnosis of polycystic ovarian syndrome (PCOS), and 4 had a combination of diagnoses, such …

Benefits Of The Enhanced Recovery After Surgery (Eras) Pathway With Quadratus Lumborum Blocks For Minimally Invasive Gynecologic Surgery Patients: A Retrospective Cohort Study, Paul S Lee, Laurie L Brunette, Intira Sriprasert, Mohamed Eloustaz, Rasika Deshpande, Crystal Adams, Laila Muderspach, Lynda Roman, Shane Dickerson, Michael P Kim

Faculty, Staff and Student Publications

STUDY OBJECTIVE: This study aimed to determine the effect of the implementation of the Enhanced Recovery After Surgery (ERAS) protocol among patients receiving minimally invasive gynecologic surgery.

DESIGN AND SETTING: This retrospective cohort study was performed in a tertiary care hospital.

PATIENTS: A total of 328 females who underwent minimally invasive gynecologic surgeries requiring at least one overnight stay at Keck Hospital of University of Southern California (USC), California, USA, from 2016 to 2020 were included in this study.

INTERVENTIONS: The institutional ERAS protocol was implemented in late 2018. A total of 186 patients from 2016 to 2018 prior to …

Care After Premenopausal Risk-Reducing Salpingo-Oophorectomy In High-Risk Women: Scoping Review And International Consensus Recommendations, Denise R Nebgen, Susan M Domchek, Joanne Kotsopoulos, Joanne A De Hullu, Emma J Crosbie, Vincent Singh Paramanandam, Monique M A Brood-Van Zanten, Barbara M Norquist, Theresa Guise, Serge Rozenberg, Allison W Kurian, Holly J Pederson, Nese Yuksel, Rachel Michaelson-Cohen, Sharon L Bober, Agnaldo Lopes Da Silva Filho, Nora Johansen, F Guidozzi, D Gareth Evans, Usha Menon, Sheryl A Kingsberg, C Bethan Powell, Giovanni Grandi, Claudia Marchetti, Michelle Jacobson, Donal J Brennan, Martha Hickey

Faculty, Staff and Student Publications

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Functional Analysis Reveals Driver Cooperativity And Novel Mechanisms In Endometrial Carcinogenesis, Matthew Brown, Alicia Leon, Katarzyna Kedzierska, Charlotte Moore, Hayley L Belnoue-Davis, Susanne Flach, John P Lydon, Francesco J Demayo, Annabelle Lewis, Tjalling Bosse, Ian Tomlinson, David N Church

Faculty, Staff and Students Publications

High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten …

Influence Of Macrophages On Vascular Invasion Of Inflammatory Breast Cancer Emboli Measured Using An In Vitro Microfluidic Multi-Cellular Platform, Manasa Gadde, Melika Mehrabi-Dehdezi, Bisrat G Debeb, Wendy A Woodward, Marissa Nichole Rylander

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help with prognosis and subsequent development of effective treatments. In this study, we present a 3D in vitro microfluidic IBC platform consisting of THP1 M0, M1, or M2 macrophages, IBC cells, and endothelial cells. The platform comprises a collagen matrix that includes an endothelialized vessel, creating a physiologically relevant environment for cellular interactions. Through the utilization of this …

Proteogenomic Insights Suggest Druggable Pathways In Endometrial Carcinoma, Yongchao Dou, Lizabeth Katsnelson, Marina A Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi-Ting Wang, Iga Kolodziejczak, Rita Jui-Hsien Lu, Chia-Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C Arend, Jasmin Bavarva, Lijun Chen, Rosalie K Chu, Andrzej Czekański, Teresa Davoli, Elizabeth G Demicco, Deborah Delair, Kelly Devereaux, Saravana M Dhanasekaran, Peter Dottino, Bailee Dover, Thomas L Fillmore, Mckenzie Foxall, Catherine E Hermann, Tara Hiltke, Galen Hostetter, Marcin Jędryka, Scott D Jewell, Isabelle Johnson, Andrea G Kahn, Amy T Ku, Chandan Kumar-Sinha, Paweł Kurzawa, Alexander J Lazar, Rossana Lazcano, Jonathan T Lei, Yi Li, Yuxing Liao, Tung-Shing M Lih, Tai-Tu Lin, John A Martignetti, Ramya P Masand, Rafał Matkowski, Wilson Mckerrow, Mehdi Mesri, Matthew E Monroe, Jamie Moon, Ronald J Moore, Michael D Nestor, Chelsea Newton, Tatiana Omelchenko, Gilbert S Omenn, Samuel H Payne, Vladislav A Petyuk, Ana I Robles, Henry Rodriguez, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Athena A Schepmoes, Tujin Shi, Zhiao Shi, Jimin Tan, Mason Taylor, Mathangi Thiagarajan, Joshua M Wang, Karl K Weitz, Bo Wen, C M Williams, Yige Wu, Matthew A Wyczalkowski, Xinpei Yi, Xu Zhang, Rui Zhao, David Mutch, Arul M Chinnaiyan, Richard D Smith, Alexey I Nesvizhskii, Pei Wang, Maciej Wiznerowicz, Li Ding, D R Mani, Hui Zhang, Matthew L Anderson, Karin D Rodland, Bing Zhang, Tao Liu, David Fenyö

Faculty, Staff and Students Publications

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

Subsequent Female Breast Cancer Risk Associated With Anthracycline Chemotherapy For Childhood Cancer, Yuehan Wang, Cécile M Ronckers, Flora E Van Leeuwen, Chaya S Moskowitz, Wendy Leisenring, Gregory T Armstrong, Florent De Vathaire, Melissa M Hudson, Claudia E Kuehni, Michael A Arnold, Charlotte Demoor-Goldschmidt, Daniel M Green, Tara O Henderson, Rebecca M Howell, Matthew J Ehrhardt, Joseph P Neglia, Kevin C Oeffinger, Helena J H Van Der Pal, Leslie L Robison, Michael Schaapveld, Lucie M Turcotte, Nicolas Waespe, Leontien C M Kremer, Jop C Teepen

Faculty, Staff and Student Publications

Anthracycline-based chemotherapy is associated with increased subsequent breast cancer (SBC) risk in female childhood cancer survivors, but the current evidence is insufficient to support early breast cancer screening recommendations for survivors treated with anthracyclines. In this study, we pooled individual patient data of 17,903 survivors from six well-established studies, of whom 782 (4.4%) developed a SBC, and analyzed dose-dependent effects of individual anthracycline agents on developing SBC and interactions with chest radiotherapy. A dose-dependent increased SBC risk was seen for doxorubicin (hazard ratio (HR) per 100 mg m

Feasibility And Clinical Acceptability Of Automation-Assisted 3d Conformal Radiotherapy Planning For Patients With Cervical Cancer In A Resource-Constrained Setting, Sikudhani Muya, Jerry Ndumbalo, Sarah Kutika Nyagabona, Shaid Yusuf, Dong Joo Rhee, Beatrice Paul Mushi, Benjamin Li, Li Zhang, Surbhi Grover, Mary Feng, I-Chow Hsu, Elia Mmbaga, Katherine Van Loon, Laurence Court, Melody Xu

Faculty, Staff and Student Publications

Purpose: The Ocean Road Cancer Institute (ORCI) in Tanzania began offering 3D conformal radiation therapy (3DCRT) in 2018. Steep learning curves, high patient volume, and a limited workforce resulted in long radiation therapy (RT) planning workflows. We aimed to establish the feasibility of implementing an automation-assisted cervical cancer 3DCRT planning system.

Materials and methods: We performed chart abstractions on 30 patients with cervical cancer treated with 3DCRT at ORCI. The Radiation Planning Assistant (RPA) generated a new automated set of contours and plans on the basis of anonymized computed tomography images. Each were assessed for edit time requirements, dose-volume safety …

Relationship Between Plasma Fluoride Levels, Glutathione Peroxidase Activity, Hemoglobin, And Abortion In Rural And Urban Pregnant Women From Settat (Morocco), Lalla Asmaa Katir Masnaoui, Abdellatif Rahim, Habiba Bouchab, Bouchra El Amiri, Boubker Nasser, Essamadi Abdel Khalid

Makara Journal of Health Research

Background: This study aimed to investigate the relationship between plasma fluoride and hemoglobin levels, glutathione peroxidase (GPx) activity, and abortion among rural and urban pregnant women from Settat province (Morocco).

Methods: Blood samples were collected from rural pregnant women who had not undergone abortion (N = 224), rural pregnant women who had an abortion (N = 38), urban pregnant women who had not undergone abortion (N = 163), and urban pregnant women who had an abortion (N = 14).

Results: The highest (p < 0.01) plasma fluoride levels and the lowest (p < 0.01) GPx activity were observed in rural pregnant women. In all participants, plasma fluoride levels were significantly higher (p < 0.001), and the GPx activity was significantly (p < 0.001) lower in pregnant women who had an abortion compared with those who did not undergo such process. No significant difference was observed between the hemoglobin levels of all participants. Furthermore, abortion was positively correlated with plasma fluoride levels (p < 0.001) and negatively correlated with GPx activity (p < 0.001) in rural participants.

Conclusions: Rural pregnant women had higher plasma …

Chromatin Architectural Factor Ctcf Is Essential For Progesterone-Dependent Uterine Maturation, Sylvia C Hewitt, Artiom Gruzdev, Cynthia J Willson, San-Pin Wu, John P Lydon, Niels Galjart, Francesco J Demayo

Faculty, Staff and Students Publications

Receptors for estrogen and progesterone frequently interact, via Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss-of-function CTCF mutation in >20% of human endometrial tumors indicates its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcf

Trim28 Modulates Nuclear Receptor Signaling To Regulate Uterine Function, Rong Li, Tianyuan Wang, Ryan M Marquardt, John P Lydon, San-Pin Wu, Francesco J Demayo

Faculty, Staff and Students Publications

Estrogen and progesterone, acting through their cognate receptors the estrogen receptor α (ERα) and the progesterone receptor (PR) respectively, regulate uterine biology. Using rapid immunoprecipitation and mass spectrometry (RIME) and co-immunoprecipitation, we identified TRIM28 (Tripartite motif containing 28) as a protein which complexes with ERα and PR in the regulation of uterine function. Impairment of TRIM28 expression results in the inability of the uterus to support early pregnancy through altered PR and ERα action in the uterine epithelium and stroma by suppressing PR and ERα chromatin binding. Furthermore, TRIM28 ablation in PR-expressing uterine cells results in the enrichment of a …

Spatial Mapping Of The Dna Adducts In Cancer, Kimiko L Krieger, Elise K Mann, Kevin J Lee, Elyse Bolterstein, Deborah Jebakumar, Michael M Ittmann, Valeria L Dal Zotto, Mohamed Shaban, Arun Sreekumar, Natalie R Gassman

Faculty, Staff and Students Publications

DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability. While mutational burden offers some insight into the level of DNA damage a cell may have experienced and subsequently repaired, it does not quantify DNA adducts and strand breaks. Mutational burden also infers the identity of the DNA damage. With advances …

Targeting Polyploid Giant Cancer Cells Potentiates A Therapeutic Response And Overcomes Resistance To Parp Inhibitors In Ovarian Cancer, Xudong Zhang, Jun Yao, Xiaoran Li, Na Niu, Yan Liu, Richard A Hajek, Guang Peng, Shannon Westin, Anil K Sood, Jinsong Liu

Faculty, Staff and Student Publications

To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)-derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell …

Radiomic And Deep Learning Characterization Of Breast Parenchyma On Full Field Digital Mammograms And Specimen Radiographs: A Pilot Study Of A Potential Cancer Field Effect, Natalie Baughan, Hui Li, Li Lan, Matthew Embury, Isaiah Yim, Gary J Whitman, Randa El-Zein, Isabelle Bedrosian, Maryellen L Giger

Faculty, Staff and Student Publications

PURPOSE: In women with biopsy-proven breast cancer, histologically normal areas of the parenchyma have shown molecular similarity to the tumor, supporting a potential cancer field effect. The purpose of this work was to investigate relationships of human-engineered radiomic and deep learning features between regions across the breast in mammographic parenchymal patterns and specimen radiographs.

APPROACH: This study included mammograms from 74 patients with at least 1 identified malignant tumor, of whom 32 also possessed intraoperative radiographs of mastectomy specimens. Mammograms were acquired with a Hologic system and specimen radiographs were acquired with a Fujifilm imaging system. All images were retrospectively …

A Crispr/Cas9-Engineered Mouse Carrying A Conditional Knockout Allele For The Early Growth Response-1 Transcription Factor, Vineet K Maurya, Yan Ying, Denise G Lanza, Jason D Heaney, John P Lydon

Faculty, Staff and Students Publications

Early growth response 1 (EGR1) mediates transcriptional programs that are indispensable for cell division, differentiation and apoptosis in numerous physiologies and pathophysiologies. Whole-body EGR1 knockouts in mice (Egr1KO) have advanced our understanding of EGR1 function in an in vivo context. To extend the utility of the mouse to investigate EGR1 responses in a tissue- and/or cell-type-specific manner, we generated a mouse model in which exon 2 of the mouse Egr1 gene is floxed by CRISPR/Cas9 engineering. The floxed Egr1 alleles (Egr1f/f) are designed to enable spatiotemporal control of Cre-mediated EGR1 ablation in the …

Unravelling Spatial Gene Associations With Seagal: A Python Package For Spatial Transcriptomics Data Analysis And Visualization, Linhua Wang, Chaozhong Liu, Yang Gao, Xiang H-F Zhang, Zhandong Liu

Faculty, Staff and Students Publications

SUMMARY: In the era where transcriptome profiling moves toward single-cell and spatial resolutions, the traditional co-expression analysis lacks the power to fully utilize such rich information to unravel spatial gene associations. Here, we present a Python package called Spatial Enrichment Analysis of Gene Associations using L-index (SEAGAL) to detect and visualize spatial gene correlations at both single-gene and gene-set levels. Our package takes spatial transcriptomics datasets with gene expression and the aligned spatial coordinates as input. It allows for analyzing and visualizing genes' spatial correlations and cell types' colocalization within the precise spatial context. The output could be visualized as …

Testis-Specific Serine Kinase 3 Is Required For Sperm Morphogenesis And Male Fertility, Kaori Nozawa, Thomas X Garcia, Katarzyna Kent, Mei Leng, Antrix Jain, Anna Malovannaya, Fei Yuan, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: The importance of phosphorylation in sperm during spermatogenesis has not been pursued extensively. Testis-specific serine kinase 3 (Tssk3) is a conserved gene, but TSSK3 kinase functions and phosphorylation substrates of TSSK3 are not known.

OBJECTIVE: The goals of our studies were to understand the mechanism of action of TSSK3.

MATERIALS AND METHODS: We analyzed the localization of TSSK3 in sperm, used CRISPR/Cas9 to generate Tssk3 knockout (KO) mice in which nearly all of the Tssk3 open reading frame was deleted (ensuring it is a null mutation), analyzed the fertility of Tssk3 KO mice by breeding mice for 4 months, …

Application Of Natural Polysaccharides And Their Novel Dosage Forms In Gynecological Cancers: Therapeutic Implications From The Diversity Potential Of Natural Compounds, Yi Li, Chuanlong Zhang, Lu Feng, Qian Shen, Fudong Liu, Xiaochen Jiang, Bo Pang

Faculty, Staff and Student Publications

Cancer is one of the most lethal diseases. Globally, the number of cancers is nearly 10 million per year. Gynecological cancers (for instance, ovarian, cervical, and endometrial), relying on hidden diseases, misdiagnoses, and high recurrence rates, have seriously affected women's health. Traditional chemotherapy, hormone therapy, targeted therapy, and immunotherapy effectively improve the prognosis of gynecological cancer patients. However, with the emergence of adverse reactions and drug resistance, leading to the occurrence of complications and poor compliance of patients, we have to focus on the new treatment direction of gynecological cancers. Because of the potential effects of natural drugs in regulating …

Histone H2a Lys130 Acetylation Epigenetically Regulates Androgen Production In Prostate Cancer, Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y Feng, Kiran Mahajan, Nupam P Mahajan

Faculty, Staff and Students Publications

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of …

Tubectomy With Delayed Oophorectomy As An Alternative To Risk-Reducing Salpingo-Oophorectomy In High-Risk Women To Assess The Safety Of Prevention: The Tuba-Wisp Ii Study Protocol, Miranda P Steenbeek, Majke H D Van Bommel, Joanna Inthout, Christine B Peterson, Michiel Simons, Kit C B Roes, Marleen Kets, Barbara M Norquist, Elizabeth M Swisher, Rosella P M G Hermens, Tuba-Wisp Ii Consortium, Karen H Lu, Joanne A De Hullu

Faculty, Staff and Student Publications

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 (BRCA1) …

Digital Health Technologies For Peripartum Depression Management Among Low-Socioeconomic Populations: Perspectives From Patients, Providers, And Social Media Channels, Alexandra Zingg, Tavleen Singh, Amy Franklin, Angela Ross, Sudhakar Selvaraj, Jerrie Refuerzo, Sahiti Myneni

Faculty, Staff and Student Publications

BACKGROUND: Peripartum Depression (PPD) affects approximately 10-15% of perinatal women in the U.S., with those of low socioeconomic status (low-SES) more likely to develop symptoms. Multilevel treatment barriers including social stigma and not having appropriate access to mental health resources have played a major role in PPD-related disparities. Emerging advances in digital technologies and analytics provide opportunities to identify and address access barriers, knowledge gaps, and engagement issues. However, most market solutions for PPD prevention and management are produced generically without considering the specialized needs of low-SES populations. In this study, we examine and portray the information and technology needs …

Cfp1 Governs Uterine Epigenetic Landscapes To Intervene In Progesterone Responses For Uterine Physiology And Suppression Of Endometriosis, Seung Chel Yang, Mira Park, Kwon-Ho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J Demayo, John P Lydon, David G Skalnik, Hyunjung J Lim, Seok-Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim, Haengseok Song

Faculty, Staff and Students Publications

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent …

Machine Learning Reveals Lipidome Remodeling Dynamics In A Mouse Model Of Ovarian Cancer, Olatomiwa O Bifarin, Samyukta Sah, David A Gaul, Samuel G Moore, Ruihong Chen, Murugesan Palaniappan, Jaeyeon Kim, Martin M Matzuk, Facundo M Fernández

Faculty, Staff and Students Publications

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. …

A Highly Selective Humanized Ddr1 Mab Reverses Immune Exclusion By Disrupting Collagen Fiber Alignment In Breast Cancer, Junquan Liu, Huai-Chin Chiang, Wei Xiong, Victor Laurent, Samuel C Griffiths, Jasmin Dülfer, Hui Deng, Xiujie Sun, Y Whitney Yin, Wenliang Li, Laurent P Audoly, Zhiqiang An, Thomas Schürpf, Rong Li, Ningyan Zhang

Faculty, Staff and Student Publications

BACKGROUND: Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models.

METHODS: To develop a DDR1-targeting mAb as a potential cancer therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding …

Conjugated Bile Acids Are Nutritionally Re-Programmable Antihypertensive Metabolites, Saroj Chakraborty, Anju Lulla, Xi Cheng, Ji-Youn Yeo, Juthika Mandal, Tao Yang, Xue Mei, Piu Saha, Rachel M Golonka, Beng San Yeoh, Blair Mell, Wei Jia, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Arun Sreekumar, Katie Meyer, Matam Vijay-Kumar, Bina Joe

Faculty, Staff and Students Publications

BACKGROUND: Hypertension is the largest risk factor affecting global mortality. Despite available medications, uncontrolled hypertension is on the rise, whereby there is an urgent need to develop novel and sustainable therapeutics. Because gut microbiota is now recognized as an important entity in blood pressure regulation, one such new avenue is to target the gut-liver axis wherein metabolites are transacted via host-microbiota interactions. Knowledge on which metabolites within the gut-liver axis regulate blood pressure is largely unknown.

METHOD: To address this, we analyzed bile acid profiles of human, hypertensive and germ-free rat models and report that conjugated bile acids are inversely …

Phase Ii Trial Of Nelipepimut-S Peptide Vaccine In Women With Ductal Carcinoma In Situ, Anne E O'Shea, Guy T Clifton, Na Qiao, Brandy M Heckman-Stoddard, Malgorzata Wojtowicz, Eileen Dimond, Isabelle Bedrosian, Diane Weber, Judy E Garber, Alexander Husband, Ricardo Pastorello, J Jack Lee, Mike Hernandez, Diane D Liu, Lana A Vornik, Powel H Brown, Gheath Alatrash, George E Peoples, Elizabeth A Mittendorf

Faculty, Staff and Student Publications

UNLABELLED: NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in …

Clinical Outcomes Of Leuprolide Acetate In The Treatment Of Recurrent Ovarian Granulosa Cell Tumors, Katherine I Foster, Alejandra Flores Legarreta, Rhea Kamat, Katelyn F Handley, Deanna Glassman, Jeffrey A How, Barrett C Lawson, Shannon N Westin, Lois M Ramondetta, Michael Frumovitz, David M Gershenson, Anil K Sood, R Tyler Hillman

Faculty, Staff and Student Publications

BACKGROUND: The optimal treatment of recurrent ovarian granulosa cell tumors is not known. Preclinical studies and small case series have suggested direct antitumor activity of gonadotropin-releasing hormone agonists in the treatment of this disease, but little is known about the efficacy and safety of this approach.

OBJECTIVE: This study aimed to describe patterns of use and clinical outcomes of leuprolide acetate in a cohort of patients with recurrent granulosa cell tumors.

STUDY DESIGN: This was a retrospective cohort study of patients enrolled in the Rare Gynecologic Malignancy Registry at a large cancer referral center and affiliated county hospital. Patients meeting …

Gastrulation Morphogenesis In Synthetic Systems, Alyssa A Emig, Margot L K Williams

Faculty, Staff and Students Publications

Recent advances in pluripotent stem cell culture allow researchers to generate not only most embryonic cell types, but also morphologies of many embryonic structures, entirely in vitro. This recreation of embryonic form from naïve cells, known as synthetic morphogenesis, has important implications for both developmental biology and regenerative medicine. However, the capacity of stem cell-based models to recapitulate the morphogenetic cell behaviors that shape natural embryos remains unclear. In this review, we explore several examples of synthetic morphogenesis, with a focus on models of gastrulation and surrounding stages. By varying cell types, source species, and culture conditions, researchers have recreated …