tbuckley/cabot-search huggingface dataset:
Abstract B046: Lack of ER/PR expression and unresponsiveness to oral contraceptives in fallopian tube stem/progenitor cell states: reevaluating the mechanism of cancer prevention
Authors: Megan Ritting, Syed Mohammed Musheer Aalam, Manny Bettencourt, Kinnera Jalagam, Scott Kaufmann, John Weroha, Mark Sherman, Jamie Bakkum-Gamez, Nagarajan Kannan
Journal: Cancer Research (2024)

Abstract Objective: Prolonged use of oral contraceptives (OC) has been associated with a reduced risk of ovarian cancer, yet the underlying mechanism remains elusive. Long-lived self-renewing fallopian tube epithelial stem cells (SCs) capable of cilio-secretory differentiation are considered a potential cell-of-origin for ovarian cancers. Using innovative stem cell methodologies, our objective is to gain insights into the mechanism by which OC exert their protective action. Methods: This research is supported by Mayo Clinic’s clinically annotated regenerative fallopian tube biobank. RNA was isolated from the SC-enriched cell fraction and differentiated cilio-secretory organoids. Absolute mRNA copies of OC targets estrogen receptor-alpha (ESR1; ER) and progesterone receptor (PGR; PR) were determined using optimum RT-ddPCR assay. OC effects on SC-enriched growth in 2D was measured using live-cell imaging. Our primary tubal cells and organoids as well as public single-cell transcriptomics datasets were analyzed for ESR1/PGR expression across tubal cell states. Results: The panel of OCs tested exhibited no growth response in patient-derived cultures enriched with stem cells, and there was an absence of ESR1/PGR expression. Clonal organoid differentiation exhibited high ESR1 levels and lack of PGR, while growth factor cocktail-dependent PGR induction was achieved. Single-cell transcriptomics identified molecular signatures associated with ER/PR-positive OC sensor cells. Conclusions: Based on our findings, we propose a model wherein ER/PR-negative SC differentiate into ER/PR-positive OC-sensors and control SC development through paracrine signals. Our in-vitro conditions to differentiate SC into OC-sensors provide an opportunity to study complex paracrine signaling and explore targets for prevention of ovarian cancers. Citation Format: Megan Ritting, Syed Mohammed Musheer Aalam, Manny Bettencourt, Kinnera Jalagam, Scott Kaufmann, John Weroha, Mark Sherman, Jamie Bakkum-Gamez, Nagarajan Kannan. Lack of ER/PR expression and unresponsiveness to oral contraceptives in fallopian tube stem/progenitor cell states: reevaluating the mechanism of cancer prevention [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B046.
Firearm Access and Gun Violence Exposure Among American Indian or Alaska Native and Black Adults
Authors: Michael D. Anestis, Jayna Moceri-Brooks, Devon Ziminski, R. Thurman Barnes, Daniel Semenza
Journal: JAMA Network Open (2024)

Importance American Indian or Alaska Native and Black adults experience elevated rates of firearm injury and death, but both groups are severely underrepresented in research on firearm exposure and behaviors. Objective To explore geodemographic differences in firearm behaviors and violence exposure among American Indian or Alaska Native and Black adults in the US. Design, Setting, and Participants In this survey study, nationally representative samples of American Indian or Alaska Native and/or Black adults recruited from KnowledgePanel were surveyed cross-sectionally. Surveys were administered online between April 12 and May 4, 2023. Main Outcomes and Measures Firearm access, storage, and carrying behaviors and lifetime firearm violence exposure were the primary outcomes. Demographic factors such as age, geographic location, and political affiliation were considered. Data were weighted to geodemographic distributions from the US Census Bureau’s 2022 Current Population Survey. Results Of 3542 participants, 527 (14.9%) were American Indian or Alaska Native (280 [53.1%] female) and 3015 (85.1%) were Black (1646 [54.6%] female). Both groups exhibited high firearm access rates (American Indian or Alaska Native adults: 238 [45.4%; 95% CI, 39.4%-51.7%]; Black adults: 909 [30.4%; 95% CI, 28.0%-32.9%]), predominantly owning handguns for home protection. The groups demonstrated similar firearm storage patterns, and a substantial proportion endorsed always or almost always carrying firearms outside the home (American Indian or Alaska Native adults: 18.9%; Black adults: 15.2%). Self-protection was a common reason for carrying a firearm (American Indian or Alaska Native adults: 104 [84.9%; 95% CI, 74.1%-91.7%]; Black adults: 350 [88.3%; 95% CI, 82.3%-92.4%]), and a minority of participants cited lack of faith in the police (American Indian or Alaska Native adults: 19 [15.2%; 95% CI, 8.2%-26.7%]; Black adults: 61 [15.4%; 95% CI, 10.3%-21.2%]), indicating potential shifts in public safety dynamics. Conclusions and Relevance In this survey study of American Indian or Alaska Native and Black US adults, a substantial percentage of both groups reported living in homes with firearms, storing firearms loaded and unlocked, frequently carrying firearms outside the home, and having been exposed directly and indirectly to gun violence. These findings underscore the need for nuanced public health campaigns and policies and highlight challenges for law enforcement in contexts of racial disparities and changing legal frameworks.
No Science Supports the Diagnostic Methods for Abusive Head Trauma—Reply
Authors: John M. Leventhal, Andrea G. Asnes, George A. Edwards
Journal: JAMA Pediatrics (2024)

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Abstract IA001: Placing our bets to make a difference
Authors: David D. Bowtell
Journal: Cancer Research (2024)

Abstract The presentation will focus genomics of high grade serous ovarian cancer (HGSC). I will briefly describe TRACEBACK, a study aimed at identifying deceased high-risk mutation carriers, and how a novel approach to patient ascertainment and testing may serve as a model for other familial cancer diseases. I will discuss some of key questions and directions arising from our studies of end-stage BRCA-related HGSC using samples collected through a rapid autopsy program. The major focus of the presentation will be on analyses of patients with exceptionally poor or favorable overall survival, including a cohort of BRCA1/2 patients with an unusually poor response to treatment and survival, and HGSC patients who survive more than 10 years following their diagnosis. Citation Format: David D. Bowtell. Placing our bets to make a difference [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA001.
Abstract B032: Probing the molecular crosstalk between ovarian cancer and omentum
Authors: Monica A. Haughan, Hannah Lusk, Tova M. Bergsten, Sarah E. Levy, Aloysius J. Klingelhutz, Laura M. Sanchez, Joanna E. Burdette
Journal: Cancer Research (2024)

Abstract Ovarian cancer (OC) is the 5th leading cause of cancer death in women despite being considered rare, highlighting the critical need to better understand the mechanisms of pathogenesis and progression. High grade serous OC, the most prevalent OC subtype, frequently metastasizes to the omentum. Building off previous work using an imaging mass spectrometry (IMS) co-culture system to uncover metabolomic changes in primary metastasis, we are now probing the molecular crosstalk between the omentum and OC cells. Our IMS co-culture system identifies molecules produced in co-culture of tumorigenic MOE PTENshRNA or vector control MOE PTENSCR cells and explants. IMS revealed multiple signals, including epinephrine (EPI), unique to the MOE PTENshRNA + omentum condition. Clinical data shows stress and increased expression of ADRβ2, an EPI receptor, are correlated with poorer survival. However, no significant changes were observed in EPI (10mM) treated MOE PTENshRNA invasiveness investigated via Boyden chamber assay. EPI signaling through ADRβ2 can induce lipolysis and propranolol treatment, antagonizing ADRβ2, has shown partial deactivation of OC stimulated lipolysis. We hypothesize EPI may be an autocrine signal produced by the omentum liberating fatty acids and driving tumor progression. To test this, we began examining an immortalized, human pre-adipocyte line (VNPAD 30315) for mechanistic studies. VNPAD 30315 can be differentiated into adipocytes and forms spheroids more accurately simulating in vivo fatty tissues compared to 2D culture. Successfully differentiated spheroids have been generated and spheroid conditioned media (CM) increases invasion like omentum CM. Preliminary results suggest spheroids produce results similar to murine and human omentum explants in IMS co-culture. Currently we are exploring the effects of EPI on the spheroids and adipocyte CM on tumorigenic models. Overall, we are working to identify signals in omental metastasis with our IMS co-culture system and to determine their mechanisms in vitro with a 3D adipocyte model. Citation Format: Monica A. Haughan, Hannah Lusk, Tova M. Bergsten, Sarah E. Levy, Aloysius J. Klingelhutz, Laura M. Sanchez, Joanna E. Burdette. Probing the molecular crosstalk between ovarian cancer and omentum [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B032.
Abstract B014: Charting ovarian cancer dependencies with patient-derived organoids
Authors: Ashley Anderson, Tate Bertea, James Neiswender, Lisa Brenan, Megan Wong, Alina Simerzin, Sarah Wie, Isabella Boyle, Lauren Golden, Barbara De Kegel, Josh Dempster, Yuen-Yi Tseng, David Root, Sarah Hill, Andrew Aguirre, Francisca Vazquez
Journal: Cancer Research (2024)

Abstract The Cancer Dependency Map aims to accelerate precision cancer medicine by identifying the landscape of cancer vulnerabilities across all tumors. To address underrepresented cancer types, we have optimized a genome-wide CRISPR KO screening pipeline, utilizing a condensed Cas12a library, for patient-derived 3D models. Here, we present characterization of a cohort of ovarian models which consist of underrepresented cancer subtypes along with treatment-resistant cancers. In particular, our organoid dataset includes low-grade serous carcinoma models, an ovarian cancer subtype that is understudied and not previously characterized in 2D DepMap screens. The increased representation of ovarian models will improve the potential of DepMap to uncover genetic drivers of ovarian cancers. Through genomic perturbation we showed that these 3D models achieved screen quality comparable to historically derived 2D models. Our methods provide a framework for screening future cancer models and discovering vulnerabilities in select patient populations. Citation Format: Ashley Anderson, Tate Bertea, James Neiswender, Lisa Brenan, Megan Wong, Alina Simerzin, Sarah Wie, Isabella Boyle, Lauren Golden, Barbara De Kegel, Josh Dempster, Yuen-Yi Tseng, David Root, Sarah Hill, Andrew Aguirre, Francisca Vazquez. Charting ovarian cancer dependencies with patient-derived organoids [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B014.
Abstract A082: Targeting sterol regulatory element binding protein 1 (SREBP1) improves response to standard-of-care chemotherapy and alters the tumor microenvironment in pre-clinical models of obesity and ovarian cancer
Authors: M. Sharon Stack, Yueying Liu, Jing Yang, Tyvette S. Hilliard, Zhikun Wang, Jeff Johnson, Wanrui Wang, Gena Dominique, Elizabeth I. Harper, Nicholas M. Stavrou, Anna Juncker-Jensen
Journal: Cancer Research (2024)

Abstract Obesity is a recognized non-infectious pandemic that increases ovarian cancer (OvCa) incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity (DIO) mouse model (Liu et al. Can.Res. 2015; 75:5046). DIO also elevated expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1), a master regulator of de novo lipogenesis and lipid homeostasis. A follow-up study using DIO models showed a significantly diminished response to standard-of-care (SOC) paclitaxel/carboplatin chemotherapy in high fat diet (HFD) mice relative to low fat diet (LFD) controls (Liu et al., J.Exp.Clin.Can.Res. 2023; 42:165). Both studies showed an effect of DIO on tumor fibrosis and immune landscape and these changes were also observed in the ovarian cancer tumors of women with high body mass index. In the current study, we have evaluated the effect of inhibitors of SREBP1 processing, in combination with SOC chemotherapy, in the context of DIO in pre-clinical models of OvCa. Our results show significantly diminished post-treatment tumor recurrence in HFD mice receiving SOC chemotherapy plus an SREBP1 processing inhibitor, with concomitant alterations in the peritoneal immune landscape. Together these data suggest that the reported negative impact of obesity on OvCa patient survival may be due obesity-induced changes in lipid regulatory factors (SREBP1) and the tumor microenvironment (immune landscape, fibrosis) that alter chemosensitivity. These data demonstrate a contribution of host obesity to ovarian tumor progression and therapeutic response and support future combination strategies targeting SREBP1, immune cells and/or fibrosis in the obese host. Citation Format: M. Sharon Stack, Yueying Liu, Jing Yang, Tyvette S. Hilliard, Zhikun Wang, Jeff Johnson, Wanrui Wang, Gena Dominique, Elizabeth I. Harper, Nicholas M. Stavrou, Anna Juncker-Jensen. Targeting sterol regulatory element binding protein 1 (SREBP1) improves response to standard-of-care chemotherapy and alters the tumor microenvironment in pre-clinical models of obesity and ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A082.
Abstract A048: Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers
Authors: Keren Bahar-Shany, Georgina D. Barnabas, Jacob Korach, Ariella Jakobson-Setton, Tamar Geiger, Keren Levanon
Journal: Cancer Research (2024)

Abstract No current screening methods for high-grade ovarian cancer (HGOC) guarantee effective early detection for high-risk women such as germline BRCA mutation carriers. Therefore, the standard-of-care remains risk-reducing salpingo-oophorectomy (RRSO) around age 40. Proximal liquid biopsy is a promising source of biomarkers, but sensitivity has not yet qualified for clinical implementation. We aimed to develop a proteomic assay based on proximal liquid biopsy, as a decision support tool for monitoring high-risk population. Ninety Israeli BRCA1 or BRCA2 mutation carriers were included in the training set (17 HGOC patients and 73 asymptomatic women), (BEDOCA trial; ClinicalTrials.gov Identifier: NCT03150121). The proteome of the microvesicle fraction of the samples was profiled by mass spectrometry and a classifier was developed using logistic regression. An independent cohort of 98 BRCA mutation carriers was used for validation. Safety information was collected for all women who opted for uterine lavage in a clinic setting. We present a 7-protein diagnostic signature, with AUC &amp;gt;0.97 and a negative predictive value (NPV) of 100% for detecting HGOC. The AUC of the biomarker in the independent validation set was &amp;gt;0.94 and the NPV &amp;gt;99%. The sampling procedure was clinically acceptable, with favorable pain scores and safety. We conclude that the acquisition of Müllerian tract proximal liquid biopsies in women at high-risk for HGOC and the application of the BRCA-specific diagnostic assay demonstrates high sensitivity, specificity, technical feasibility, and safety. A similar classifier for an average-risk population is warranted. Citation Format: Keren Bahar-Shany, Georgina D. Barnabas, Jacob Korach, Ariella Jakobson-Setton, Tamar Geiger, Keren Levanon. Utero-tubal lavage proteomic analysis: detection of ovarian cancer in BRCA mutation carriers [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A048.
Abstract B107: Elucidating the influence of long-chain fatty acids on ovarian cancer progression
Authors: Jumpei Ogura, Koji Yamanoi, Mana Taki, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai
Journal: Cancer Research (2024)

Abstract Objective: High-fat diets have been associated with cancer progression. Yet, studies indicate that the effects can differ based on the type of fat involved, such as saturated versus unsaturated fatty acids. Uncovering the role of fatty acids may help guide nutrition and provide dietary therapy for cancer patients. In this study, we investigated the effect of common long-chain fatty acids, stearic acid (SA) and oleic acid (OA), on ovarian cancer (OC). Methods: We evaluated the cytotoxicity of SA and the effects of OA using IC50, a 72-hour proliferation assay, flow cytometry, and western blot. The concentration of fatty acids within the tumor was measured using liquid chromatography-mass spectrometry (LC/MS). CAY10566 was used to inhibit SCD1, the enzyme that converts SA to OA. In vivo, tumor growth was analyzed in human OC cell lines and patient-derived xenografts (PDX) using a mouse model fed with a normal diet (ND), an SA-rich diet, or an OA-rich diet combined with CAY10566. The SA-rich diet, which we specially created, had a stearic acid concentration of 33%. Results: SA displayed prominent cytotoxicity compared to other fatty acids. SA dose-dependently increased unfolded protein response (UPR) marker expression. Adding 1μM CAY10566 increased intracellular SA, decreased OA, and reduced IC50 to 20μM (p&amp;lt;0.05). CAY10566 significantly enhanced the cytotoxicity of SA, but the addition of exogenous OA canceled the increase in cell toxicity and UPR marker expression induced by SA (p&amp;lt;0.05). In vivo, tumor growth of OC cell lines and PDXs was significantly suppressed in the SA-rich with CAY10566 group compared to the ND group (p&amp;lt;0.05), while this suppression was nullified in the OA-rich with CAY10566 group. As confirmed by LC/MS, the stearic acid concentration significantly increased in the SA-rich group. Immunohistochemistry demonstrated that CHOP, gH2AX, and caspase-3 expression significantly increased in the SA-rich with CAY10566 group and dramatically decreased in the OA-rich with CAY10566 group (p&amp;lt;0.01). Conclusion: An ectopic supply of SA inhibits OC growth via UPR, while OA counteracts this effect. Creating a Stearate-rich/Oleate-limited environment through diet might affect tumor growth in vivo. Dietary content may greatly contribute to altering function in cancer. Citation Format: Jumpei Ogura, Koji Yamanoi, Mana Taki, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Masaki Mandai. Elucidating the influence of long-chain fatty acids on ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B107.
Abstract A050: MicroRNA as biomarkers in early detection and personalized treatment in ovarian cancer: Development of a personalized prevention consortium
Authors: Renée Turzanski Fortner, Hilde Langseth
Journal: Cancer Research (2024)

Abstract Epithelial ovarian cancer (EOC) has poor survival given no effective early detection strategies and non-specific early disease symptoms. We have formed a consortium with European and American partners to provide the necessary validation of a microRNA (miRNA) panel for earlier detection of EOC using serum samples and data from prospective cohorts, paired with clinical data and biospecimens. Our objectives are to validate a serologic miRNA panel that, together with CA125, would have sufficient diagnostic discrimination to be used as a tool that, complementary to imaging, would allow early identification and direction of patients with suspected malignancy to personalized gyn-oncological care. We will validate serum miRNA profiles as biomarkers for early detection in samples collected from cases ⇐3 years prior to EOC diagnosis and matched controls and characterize sources of variation in miRNA profiles and their impact on discrimination. Evaluate miRNA profiles in the clinical setting and the discrimination between EOC cases and women with (i) benign ovarian tumors in blood samples collected prior to diagnostic surgery and (ii) underlying comorbidities (including other cancer types). Further, we will evaluate serum miRNA profiles as predictors of recurrence and will compare tumor tissue and serum miRNA profiles. Develop and optimize protocols for data integration and methods for algorithm development. Direct in silico validation, including miRNA and CA125 levels, and clinical and epidemiologic data. Address Ethical, Legal and Social Aspects (ELSA), including activities in key stakeholder groups. Challenges in health data privacy and sharing, including for development of an artificial intelligence model, will be addressed, as will the definition of a “healthy” population with respect to miRNA profiles for EOC. The consortium was launched in 2023, with the first findings expected in 2024. Beyond the initial direct aims of the consortium, expanded aims on further promising markers are envisaged. Citation Format: Renée Turzanski Fortner, Hilde Langseth. MicroRNA as biomarkers in early detection and personalized treatment in ovarian cancer: Development of a personalized prevention consortium [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A050.