tbuckley/cabot-search huggingface dataset:
Abstract 2970: Anti-diabetic drug, semaglutide, prevents doxorubicin-induced endothelial cell toxicity
Authors: Sandra Bakhit, Chelsea Amaefuna, Kota Ramana
Journal: Cancer Research (2024)

Abstract Doxorubicin (Dox) is part of the anthracycline drug family and is known for its broad and effective use as a chemotherapeutic agent. It is commonly used to treat solid tumors and malignancies such as leukemia, breast, lung, and ovarian cancers. Unfortunately, its use in treating advanced cancers is limited due to its cardiotoxic side effects. Therefore, various adjuvant approaches are required to increase Dox's efficacy and to reduce unwanted toxicities including cardiotoxicity. Semaglutideis a glucagon-like peptide-1 (GLP-1) receptor agonist commonly used to treat type-2 diabetes. In his study, the effect of Semaglutide in preventing Dox-induced endothelial cell toxicity was investigated. Our data indicate that Semaglutide prevents Dox-induced cell death in human umbilical vein endothelial cells (HUVEC) in a dose- and time-dependent manner. Similarly, live and dead cell staining assay also confirms Semaglutide prevents Dox-induced endothelial cell death. Semaglutide also prevented the Dox-induced apoptosis of HUVECs. It also prevented the Dox-induced reactive oxygen species and activation of caspase-3. Further, Semaglutide regulated the expression of various anti- and pro-apoptotic and inflammatory factors induced by Dox. Inconclusion, our current results suggests that the anti-diabetic drug, Semaglutide, could prevent Dox-induced endothelial cell death by regulating the expression of various pro-apoptotic, anti-apoptotic and inflammatory markers. Thus, our data indicate that Semaglutide could be used as a potential adjuvant drug to reduce the adverse effects of anthracycline chemotherapeutic drugs. Citation Format: Sandra Bakhit, Chelsea Amaefuna, Kota Ramana. Anti-diabetic drug, semaglutide, prevents doxorubicin-induced endothelial cell toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2970.
Abstract 7347: A transcriptome correlation network analysis of the high grade serous ovarian tumor immune microenvironment
Authors: Kaylin M. Carey, Eric B. Dammer, Corey Young, Rajesh Singh, Ti'ara Griffen, James W. Lillard
Journal: Cancer Research (2024)

Abstract High Grade Serous Ovarian Cancer (HGSOC) affects many women and is the most common and lethal histopathological type of ovarian cancer. The molecular subtypes delineated by TCGA–mesenchymal, proliferative, immunoreactive, and differentiated subtypes, offer a sophisticated and innovative framework for HGSOC classification. These subtypes not only provide a detailed molecular characterization but also contribute to understanding the HGSOC Tumor Immune Microenvironment (TIME), comprised of both immune and tumor cells. The interplay within the TIME significantly influences pro- or anti-tumor responses, creating an important link between molecular landscape and dynamic immune-tumor interactions. Currently, there is a lack of understanding for the key drivers of clinical outcomes, molecular phenotypes, and diagnostic biomarkers for HGSOC. Here, we answer the question, does immune cell type, and proportion, drive clinical and molecular subtyping of primary HGSOC? Primary ovarian tumor samples from The Cancer Genome Atlas, TCGA (n=358) samples were collected and RNA-sequenced. FPKM values were used to construct the Weighted Gene Correlation Network Analysis (WGCNA), Gene Ontology (GO) and Proportion Estimations of Immune and Cancer cells (EPIC). Enrichment of HGSOC network module overlaps using a Fischer Exact Test were used to identify novel components of HGSOC progression that were significantly associated with clusters of highly correlated gene expression profiles, HGSOC stage, grade, and molecular phenotypes. We show genes associated with T cell proliferation (CD84) and B cell regulation (CD37), epithelial to mesenchymal transition (DOCK2), adaptor proteins present in T cells and myeloid cells (LCP2), inflammatory and metabolic signaling modulators (AIF1,CD53, SASH3), immunosuppressors of T lymphocytes and dendritic cells (FGL2), cell proliferation (PI3K) and relevant tertiary lymphoid structure gene (TNFAIP8L2) significantly correlated with HGSOC progression in both estimated tumor and proportions of immune cells. Future studies aim to confirm phosphorylation cascades associated with the aggressive molecular phenotypes of HGSOC and immune cell pathobiology. Citation Format: Kaylin M. Carey, Eric B. Dammer, Corey Young, Rajesh Singh, Ti'ara Griffen, James W. Lillard. A transcriptome correlation network analysis of the high grade serous ovarian tumor immune microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7347.
Abstract 4081: rhIL-7-hyFc (efineptakin-alfa, NT-I7) increases tumor-specific CD8+ T cells despite FOLFOX cytotoxicity effect
Authors: Soung-Min Lee, Miyoung Kim, Sara Ferrando-Martínez, Sun-Kyoung Im, Mankyu Ji, Donghoon Choi
Journal: Cancer Research (2024)

Abstract rhIL-7-hyFc (efineptakin-alfa; NT-I7) is a potent T cell amplifier, comprised of two molecules of interleukin-7 (IL-7) fused to the hybrid Fc domain of IgD/IgG4 immunoglobulin. NT-I7 safely, significantly, and persistently increases the absolute lymphocyte counts (ALC) in humans in a dose-proportional manner. Importantly, this increase is primarily due to an increase in T cells (1). Previous studies have shown that NT-I7 not only significantly increases the number of CD8+ T cells in peripheral blood but also dramatically boosts the presence of tumor-infiltrating CD8+ T cells, including both tumor-specific (p15E+PD-1+) and tumor non-specific (PD-1-) CD8+ T cells in mice (2). FOLFOX is a chemotherapy regimen composed of 5-fluorouracil, leucovorin, and oxaliplatin that inhibits DNA duplication and eradicates rapidly dividing cells (3). Although the mechanism of FOLFOX results in direct tumor killing, it also has the potential to kill newly dividing lymphocytes during NT-I7 treatment (4-6). Therefore, in this study, we aimed to evaluate the feasibility of combining FOLFOX with NT-I7 in a syngeneic MC38 mouse tumor model. Our results show that NT-I7 improves the efficacy of FOLFOX, irrespective of the timing of NT-I7 administration: simultaneous administration or delayed 3 hours, or 2 days after FOLFOX administration. This improvement persists despite a significant decrease in ALC for the first 6 days, which was significantly lower than the ALC observed with FOLFOX alone. FOLFOX decreases the absolute numbers of tumor non-specific CD8+ T cells. However, adding FOLFOX does not affect the NT-I7-driven increase of tumor-specific CD8+ T cells within the tumor. Taken together, our data demonstrate that FOLFOX does not compromise NT-I7’s ability to increase tumor-specific T cells within the tumor and the combination enhances the anti-tumor response irrespective of the timing of NT-I7 administration. Citation Format: Soung-Min Lee, Miyoung Kim, Sara Ferrando-Martínez, Sun-Kyoung Im, Mankyu Ji, Donghoon Choi. rhIL-7-hyFc (efineptakin-alfa, NT-I7) increases tumor-specific CD8+ T cells despite FOLFOX cytotoxicity effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4081.
Abstract 6296: Biomarkers associated with atherosclerosis-related cardiovascular dysfunction in cancer survivors treated with anthracyclines
Authors: Kerryn W. Reding, Alexi Vasbinder, Nathaniel O'Connell, Biniyam Demissei, Warren Szewczyk, Richard Cheng, Amy Ladd, Alexander Lucas, Juergen Meyer, Stephen Bowen, Fadi Salloum, Ralph D'Agostino, Glenn Lesser, Kathryn Weaver, Bonnie Ky, W. H. Wilson Tang, W. Gregory Hundley
Journal: Cancer Research (2024)

Abstract Introduction: Cancer survival has increased in part due to treatment advances. However, anthracycline chemotherapy increases cardiovascular (CV) morbidity risk, including atherosclerotic CV disease (ASCVD). Among those receiving anthracyclines, it is yet unclear who is at greatest risk of ASCVD, a major cause of CV mortality. Elucidating pathophysiologic processes involved in the development ASCVD could shed light on strategies to identify those at risk. Methods: Analyses were performed on 279 lymphoma and breast cancer survivors enrolled in the PREVENT study [clinical trial WF-98213) through Wake Forest NCI Community Oncology Research Base (NCORP) and Alliance (A221501)]. CV dysfunction was measured via cardiac MRI (cMRI) at baseline (pre-treatment) and 6-months post-diagnosis to ascertain aortic distensibility and wall thickness in the descending aorta. Biomarkers were measured at baseline and 6-months and were log-transformed to base 2. Multiple linear regression was used to determine associations between biomarker and outcome at 6 months, adjusted for baseline biomarker and cMRI outcome, age, race, sex, body mass index, and smoking history. Results: The mean age (SD) of cancer survivors 49 (12) years; 92% were women. The mean aortic distensibility and mean wall thickness at baseline was 0.002 (0.0014) and 2.99 (0.41), respectively. Table 1 shows the associations between biomarkers and aortic distensibility and wall thickness of the descending aorta. After adjustment for confounders, Arginine, CRP, MPO, and ornithine were associated with 6-month aortic distensibility, and the HDL and SDMA were associated with aortic wall thickness. Conclusions: The findings of this study suggest that biomarkers in oxidative stress and inflammatory pathways may be involved in pathophysiology of ASCVD among cancer survivors receiving anthracyclines. These results require further study in larger cohorts to better define mechanistic pathways involved. Association of Biomarkers with Atherosclerosis-Related Cardiovascular Dysfunction Citation Format: Kerryn W. Reding, Alexi Vasbinder, Nathaniel O'Connell, Biniyam Demissei, Warren Szewczyk, Richard Cheng, Amy Ladd, Alexander Lucas, Juergen Meyer, Stephen Bowen, Fadi Salloum, Ralph D'Agostino, Glenn Lesser, Kathryn Weaver, Bonnie Ky, W. H. Wilson Tang, W. Gregory Hundley. Biomarkers associated with atherosclerosis-related cardiovascular dysfunction in cancer survivors treated with anthracyclines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6296.
Abstract 3049: Similarities between ovarian cancer and endometriosis: The role of STAT3
Authors: Allison A. Kloeckner, Sarah R. Walker
Journal: Cancer Research (2024)

Abstract Endometriosis is a painful gynecological disease that affects over 190 million women worldwide. This disease is classified by the presence of endometrial-like cells growing in and around the female reproductive system. Instead of lining the uterus, these ectopic cells shed off and cluster together forming lesions that attach to different surfaces of the female reproductive system. In particular, endometriosis cells interact with and form lesions within the mesothelial cells that line the peritoneum. There is currently no cure, and many of the therapies aiming to help with pain management come with unfavorable tradeoffs. Our research on ovarian cancer led us to investigate potential overlapping characteristics with endometriosis. Growing ovarian cancer cells in 3D causes spheroids to form which mimic the physical features of tumors and are also able to better represent cell-cell and cell-environment interactions. Analysis of the endometriosis cell lines 12Z and hEM3 demonstrated that they could also form spheroids. As both ovarian cancer cells and endometriosis cells interact with mesothelial cells, we wanted to determine if endometriosis spheroids were able to clear the mesothelial layer comparable to ovarian cancer spheroids. Evaluation of 12Z and hEM3 cell lines demonstrated that endometriosis spheroids were able to undergo mesothelial clearance. While the exact cause of endometriosis is not known, different proteins have been identified as important factors in the progression of endometriosis. The Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor involved in cell differentiation, proliferation, apoptosis resistance, angiogenesis, and metastasis. In endometriosis cell lines, STAT3 is constitutively active, which makes it a promising potential therapeutic target. To verify that STAT3 is important in endometriosis, siRNA was used to reduce the expression of STAT3 in two endometriosis cell lines, 12Z and hEM3. Both cell lines showed a decrease in cell viability. In addition, reducing the expression of STAT3 in the endometriosis cells appeared to decrease mesothelial clearance ability. Our lab previously identified statins as potential STAT3 inhibitors by using the Broad Institute’s CLUE tool. After statin treatment, 12Z and hEM3 spheroids showed a decrease in cell viability and clearance ability. Taken together, these data suggest that STAT3 plays a key role in endometriosis and that the repurposing of statins may provide a benefit to patients with endometriosis. Citation Format: Allison A. Kloeckner, Sarah R. Walker. Similarities between ovarian cancer and endometriosis: The role of STAT3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3049.
Abstract 6840: Automated preparation of single nuclei from FFPE samples for snRNA-Seq
Authors: Stevan Jovanovich, Nate Pereira, Danielle Meyer, Catherine Snopkowski, Ignas Masilionis, Brigita Meškauskaitė, Meril Takizawa, Zaki Abou-Mrad, Kenny Yu, Viviane Tabar, Kathleen Luckett, Karuna Ganesh, Nabiha Khan, Ronan Chaligne
Journal: Cancer Research (2024)

Abstract S2 Genomics developed the Singulator™ 100 and 200 Systems to automate the processing of fresh, frozen, or OCT tissues into single cell or single nuclei suspensions using disposable cartridges, reagents, and customizable protocols. The systems have been used to prepare cells or nuclei from a wide range of tissues and organisms, including human, mouse, chicken, insects, snails, zebrafish, and plants. Formalin-fixed, paraffin-embedded (FFPE) tissues are the preferred format for pathologists and as many as one billion FFPE slides are in repositories. FFPE tissue samples have traditionally been difficult to study with molecular techniques due to the chemical modifications caused by the formalin fixation, which can lead to degradation and sequestration of RNA and DNA. Recent advances in single cell/nuclei RNA-Seq library preparation technology have made it possible to overcome these challenges and generate high-quality single cell or nuclei genomic data from FFPE samples. Protocols have been released for processing previously deparaffinized and rehydrated FFPE samples on the Singulator 100 or 200 into single nuclei. We now report the development of a fully automated workflow for the deparaffinization and rehydration of FFPE tissues in about 40 min, with an optional enzymatic treatment of 45 min, and processing of FFPE tissues into singulated cells or nuclei on prototype Singulator 200 systems. Data will be presented for the optimization of process parameters for cell or nuclei recovery and RNA quality for six tissues. Finally, single nuclei sequencing data will be presented for snRNA-Seq libraries from healthy and cancerous human FFPE samples including glioblastomas and colorectal cancer. These data demonstrate the successful recovery of genomic materials from FFPE samples using an automated sample preparation system for single cell/nuclei transcriptomics. Citation Format: Stevan Jovanovich, Nate Pereira, Danielle Meyer, Catherine Snopkowski, Ignas Masilionis, Brigita Meškauskaitė, Meril Takizawa, Zaki Abou-Mrad, Kenny Yu, Viviane Tabar, Kathleen Luckett, Karuna Ganesh, Nabiha Khan, Ronan Chaligne. Automated preparation of single nuclei from FFPE samples for snRNA-Seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6840.
Abstract 7149: Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers
Authors: Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee
Journal: Cancer Research (2024)

Abstract Harnessing synthetic lethality offers an innovative approach to targeted cancer treatment. USP1, a specific deubiquitinating enzyme, has gained attention as a potential synthetic lethality target for BRCA-mutated cancers. At AIGEN Sciences, Inc., we've integrated the advanced capabilities of our human-in-the-loop (HITL) AI drug discovery platform, AIGEN ChemTailor. This cutting-edge platform thrives on continuous learning enhanced by expert feedback, refining our approach to drug discovery. Using AIGEN ChemTailor, we synthesized a specific USP1 inhibitor. Its inhibitory capabilities were validated through the Ubiquitin-rhodamine 110 assay. Notably, our inhibitor presented remarkable anti-proliferative effects on BRCA1 mutant cells (MDA-MB-436) while showing no activity against BRCA wild-type cells (HCC1954), highlighting its specificity. The efficacy of our inhibitor was enhanced when combined with PARP inhibitors, such as olaparib or AZD5305, especially in UWB1.289 cells. Impressively, the USP1 inhibitor also effectively targeted PARPi-resistant cell lines, including A2780-ola, UWB1.289-nir, HCC38-ola, MDA-MB-468-ola, U251MG-ola, and OVCAR8-ola. Clonogenic assays with MDA-MB-436 and MCF-10A emphasized our inhibitor's selectivity towards BRCA mutant phenotypes. Subsequent studies demonstrated the compound's mechanism: inducing replication stress by impairing of DNA synthesis and activating DNA damage pathways via ATR signaling. Preclinical mouse studies highlighted favorable pharmacokinetics and involved the assessment of anti-tumor effects in animal models. In summation, our USP1 inhibitor, developed using AIGEN ChemTailor and advanced molecular modeling techniques, stands out as a potent therapeutic against BRCA-mutated cancers and PARP inhibitor-resistant strains. Citation Format: Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee. Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7149.
Abstract 920: Insights from the National Cancer Institute’s request for information on existing data sharing processes for NIH-funded research
Authors: Mousumi Ghosh, Nathan Boyd, Subhashini Jagu
Journal: Cancer Research (2024)

Abstract Data sharing plays a crucial role in accelerating biomedical research discoveries, promoting rigorous and reproducible research, enabling research data reuse, and fostering public trust. To facilitate data sharing, a coordinated, sustainable, and streamlined infrastructure is required to store, preserve, retrieve, and make data findable, accessible, interoperable, and reusable. Starting January 25, 2023, researchers funded by the National Institutes of Health (NIH) are required to comply with the NIH Data Management and Sharing Policy (https://sharing.nih.gov/data-management-and-sharing-policy/about-data-management-and-sharing-policies/data-management-and-sharing-policy-overview) and indicate how research data funded by the NIH will be managed and broadly shared. As institutions prepare to meet these requirements, the National Cancer Institute (NCI) is looking to understand the existing processes of data storage, preservation, and sharing including what infrastructure and services are available to facilitate data sharing. To carry out this goal, the NCI’s Office of Data Sharing (ODS), dedicated to promoting responsible and efficient sharing of cancer research data, issued a Request for Information (RFI) to understand the existing data sharing processes for NIH-Funded Research. The RFI was designed to collect information on services (e.g. guidance on data standards and file formats), technologies (e.g. storage, compression, retrieval, archival, analysis tools, workbenches), and processes (e.g. governance, communication, education, outreach) that promote data sharing. ODS utilized the RFI to gather input from stakeholders involved in facilitating data sharing. This included personnel from various fields such as research laboratories, scientific instrumentation core facilities, offices of research and/or sponsored programs, provost offices or other research administration, libraries, information technology, and institutional review boards. We also engaged with bioinformaticians and data scientists who are actively contributing to data curation, formatting, and analysis. Here, we present analysis of the responses received, including insights relating to gaps and challenges in data sharing, and proposed next steps and recommendations. Citation Format: Mousumi Ghosh, Nathan Boyd, Subhashini Jagu. Insights from the National Cancer Institute’s request for information on existing data sharing processes for NIH-funded research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 920.