bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6153: Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead
Authors: Ranganathan Santhalakshmi , Kornienko Alexander , Evidente Antonio , Romo Daniel , Taube Joseph 
Published: April 2023

Abstract
Triple negative breast cancer (TNBC) has fewer treatment options than other types of invasive breastcancer. Moreover, Epithelial to Mesenchymal Transition (EMT) helps enrichment of cancer stem cells(CSCs) which promotes resistance to chemotherapy. Ophiobolin A (OpA), a drug like small molecule wasrecently found to have anti-CSC properties. Our current study investigated the cell death mechanism(s)induced by OpA in various breast cancer cell lines with respect to epithelial-mesenchymal transition(EMT).The mechanism of cell death elicited by OpA was analyzed by applying inhibitors for specific pathwaysincluding apoptosis, necroptosis and paraptosis and by analyzing markers of cell death using flowcytometry and western blotting. HMLE(R) and HMLE(R)-Twist cell lines were used to assay the role of EMT.The formation of necrosomes was analyzed with exogeneous expression of RIPK3 tagged with greenfluorescence protein (GFP) in HeLa cell line which lacks endogenous RIPK3 expression. The necrosomeformation was identified by formation of puncta using confocal microscopy. Immune compromised SCIDmice were used to analyze the effect of OpA In vivo.The data obtained in the present study indicates that OpA has an increased anticancer effect in TNBCcompared to the estrogen receptor (ER) positive breast cancer cells. Cells having undergone EMT wereshown to have more sensitivity towards OpA when compared to -uninduced cell lines, which is sensitiveto Necrostatin-1, an inhibitor of necroptosis. OpA also diminished the CD44hi/CD24lo population in TNBCcells. However, apoptosis and paraptosis inhibitors failed to rescue cell death which clearly confirms thatOpA induces necroptosis cell death pathway in EMT undergone cells. An increased phosphorylation ofRIPK, a necroptosis protein marker, was observed on OpA treatment compared to the control. OpAtreatment significantly increased puncta TNBC compared to the untreated control cells, furtherconfirming the necroptotic cell death in TNBC. OpA treatment showed a significant tumor regression intumor bearing SCID mice. All together our findings identify that OpA induce necroptosis in EMT-enrichedTNBC. The study further needs an in-depth analysis of involvement of EMT in necroptotic cell death inTNBC.Key words: Triple-negative breast cancer, EMT, Ophiobolin A, Necroptosis, cell deathmechanism
Citation Format: Santhalakshmi Ranganathan, Alexander Kornienko, Antonio Evidente, Daniel Romo, Joseph Taube. Triple negative breast cancer targeted by Ophiobolin A: Epithelial-mesenchymal transition take the lead. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6153.
Abstract 6388: High dose acetaminophen with n-acetylcysteine rescue inhibits M2 polarization of tumor associated macrophages
Authors: Neuwelt Alexander , Bryan Allyn , Lee Won , Pingali Pavani , Li Howard , Patel Bhaumik 
Published: April 2023

Abstract
Background: High dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue is among the few treatments that has shown a signal of activity in phase I trials (21% response rate, 3/14 assessable patients) without achieving dose limiting toxicity that has not progressed to evaluation in later line studies. We have previously shown that high dose AAP selectively depletes glutathione in the liver but not the tumor, suggesting that NAC, the FDA-approved antidote for AAP toxicity and a glutathione precursor, may selectively rescue the normal liver but not the tumor from high dose AAP. While the anti-tumor effects of AAP/NAC appear to not be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized.
Methods: In vitro the effects of Vehicle, AAP, or AAP/NAC was evaluated on bone marrow derived macrophages polarized to M2 and M1 phenotypes using IL-4 or IFN/LPS, respectively. Tumor cell viability was assessed with MTT assay. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling, and downstream gene and protein expression was studied. In vivo, effects of AAP/NAC on tumor size and tumor associated macrophage polarization were characterized in orthotopic triple negative breast tumor models 4T1 and EF43.fgf4 using cytokine elisa of tumor lysate and flow cytometry.
Results: NAC reversed AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes (such as CCL24, YM1 and arginase) and proteins (arginase, PD-L2, and CD206). However, AAP/NAC did not inhibit IFN/LPS induction of M1-associated genes (IL-6, TNF, IL-12) and proteins (INOS, PD-L1, MHC I, and CD64). In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple negative breast tumors. Flow cytometry of tumor associated macrophages revealed that AAP/NAC selectively inhibited M2 but not M1 polarization. ELISA of tumor lysate demonstrated relatively stable expression of IFN gamma but markedly suppressed expression of IL-10 in the tumor immune microenvironment.
Conclusion: Our study is the first to show that at high doses AAP/NAC has profound effects on the tumor immune microenvironment that may facilitate immune-mediated inhibition of tumor growth.
Citation Format: Alexander Neuwelt, Allyn Bryan, Won Lee, Pavani Pingali, Howard Li, Bhaumik Patel. High dose acetaminophen with n-acetylcysteine rescue inhibits M2 polarization of tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6388.
Abstract 6424: Immune characteristics and anti-PD-1-induced reinvigoration capacity of tumor-infiltrating lymphocytes in ovarian clear cell carcinoma relative to high-grade serous ovarian carcinoma
Authors: Park Junsik , Lee Yong Jae , Kim Jung Chul , Lee Jung-Yun 
Published: April 2023

Abstract
Recent clinical trials have demonstrated the potential efficacy of immune checkpoint inhibitors (ICIs) for ovarian clear cell carcinoma (OCCC). However, little is known about the immune characteristics of OCCC. In this study, we aimed to investigate the distinct immune characteristics of tumor-infiltrating lymphocytes (TILs) in OCCC to high-grade serous ovarian carcinoma (HGSOC). We isolated peripheral blood mononuclear cells (PBMCs) and TILs from patients with epithelial ovarian cancer. The expression of immune checkpoint receptors and T-cell transcription factors of TILs in OCCC (n=26) and HGSOC patients (n=44) were accessed using flow cytometry. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1 and/or anti-CTLA-4, and their proliferation was assessed to predict response to ICIs. CD8 TILs and tumor-infiltrating regulatory T cells (Tregs) exhibited higher expression of immune checkpoint receptors, including PD-1, CTLA-4, and 4-1BB, compared to PBMCs. Tregs were more infiltrated in advanced/recurrent stage than early stage OCCC. However, immune characteristics of CD8 TILs and Tregs were not significantly different regardless of stage. When we compared the characteristics of TILs in OCCC (n=26) with those in HGSOC (n=44), the expression of PD-1 on CD8 TILs was significantly lower in OCCC than in HGSOC. The frequencies of PD-1highCD8 TILs and PD-1+TOX+CD8 TILs were also lower in OCCC than HGSOC. In ex vivo assay (n=19), 9 cases responded to anti-PD-1 in terms of enhanced proliferation capacity of CD8 TILs. In addition, when anti-CTLA-4 was added to anti-PD-1, an additional increase in proliferation of CD8 TILs was observed in patients who responded to anti-PD-1. Responders to anti-PD-1 had significantly lower frequencies of effector Tregs in the TILs than non-responders. Overall, CD8 TIL in OCCC was found to be less exhausted than HGSOC in terms of PD-1 and TOX expressions. Tumor-infiltrating Tregs affected on reinvigoration ability of CD8 TILs upon ICIs treatment in OCCC. This study provides the rationale and evidence for establishing the optimal strategies for ICIs treatment in patients with OCCC.
Citation Format: Junsik Park, Yong Jae Lee, Jung Chul Kim, Jung-Yun Lee. Immune characteristics and anti-PD-1-induced reinvigoration capacity of tumor-infiltrating lymphocytes in ovarian clear cell carcinoma relative to high-grade serous ovarian carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6424.
Abstract 6529: Early life liver proteomic signature and minerals mitigation of liver injury
Authors: Harber Isabelle , McClintock Shannon D. , Knibbs Randall N. , Varani James , Aslam Muhammad N. 
Published: April 2023

Abstract
Background and Aims: Previous long-term murine (12- and 18-month) studies in C57BL/6 mice have demonstrated the beneficial role of Aquamin, a red marine algae-derived multi-mineral supplement containing calcium, magnesium, and 72 additional trace elements, in inhibiting liver tumor formation in mice on high-fat, Western-style diet (HFWD). Liver tumor incidence in mice on HFWD was decreased to 12% with the addition of Aquamin supplementation compared with 48% in the HFWD mice. Similarly, in mice on the low-fat diet, tumor incidence was only 16% and Aquamin further reduced it to 4%. Recently, we assessed the safety and tolerability of Aquamin in human subjects in a 90-day interventional trial and there was no evidence of potential liver harm, measured by liver enzymes. A short-term (16-week) mouse study was carried out to investigate early protein changes in the liver that may play a role in liver tumorigenesis and how Aquamin can interfere with that signature.
Methods: Male MS-NASH mice were maintained on a HFWD for 16 weeks with and without red algae-derived minerals. A cohort of C57BL/6 mice maintained on a standard chow (low-fat diet) was used as a control. At the end of the in-life portion of the study, body weight, liver weight, liver enzyme levels and liver histology were assessed. Samples obtained from individual livers were subjected to Tandem Mass Tag labeling and quantitative proteomics mass spectrometry.
Results: As expected, no tumors were observed at 16 weeks. Mice on the HFWD demonstrated multiple protein changes associated with dysregulated fat and carbohydrate metabolism, lipotoxicity and oxidative stress. In mice receiving Aquamin-supplementation along with the HFWD, there was reduced liver toxicity as evidenced by a decrease in levels of several cytochrome P450 enzymes and other oxidant-generating moieties. Additionally, multiple keratins, which provide cytoskeletal support were elevated. Phosphate and tensin homolog (PTEN), a tumor suppressor, was upregulated with Aquamin. There was an upregulation of several pathways implicated in tumor suppressor activity, notably keratinization, hedgehog signaling in the off-state, and regulation of PTEN stability and activity.
Conclusions: The proteomic expression of the livers of HFWD mice in this short-term study explains early protein changes that may contribute to liver cancer and the potential mechanisms by which dietary minerals may mitigate such down-stream effects.
Citation Format: Isabelle Harber, Shannon D. McClintock, Randall N. Knibbs, James Varani, Muhammad N. Aslam. Early life liver proteomic signature and minerals mitigation of liver injury [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6529.
Abstract 6592: An AI platform for vascular and fibrosis analysis of pathology images
Authors: Zheng Yawen , Zhang Likun , Wang Dawei , Gao Sheng 
Published: April 2023

Abstract
Introduction: Changes in the number of blood vessels and the proportion of fibrosis regions in xenograft tumors are key indicators for efficacy of oncology drugs, which currently are assessed mainly by human visual examination that is time-consuming, inaccurate and biased because only part of a pathology image is checked. We developed an online AI platform that integrates machine learning algorithms in Computer Vision to quickly and automatically obtain accurate and comprehensive information on blood vessels and fibrosis regions from a whole pathology image.
Methods: In a stained pathology image, blood vessels are stained with a different color than other components (e. g. connective tissues, tumor cells, background), so we can directly locate pixels representing them. They also have different topological structures, so we can outline and count the contours of vessels. To count the number of vessels more precisely and reduce the interference of noise, we keep a contour only if it intersects with some located pixels and the number of pixels in the intersection exceeds an adjustable threshold. The fibrosis regions are identified by color contrast since they are stained with a distinct and easily recognizable color. The algorithms were implemented using the OpenCV package.
Results: Our AI platform automatically annotates blood vessels and fibrosis regions in pathology images, and generates reports in excel format to report the number and total area of blood vessels, the area and ratio of fibrosis regions, and execution time. It demonstrates superior performance to standard pathology software.
Citation Format: Yawen Zheng, Likun Zhang, Dawei Wang, Sheng Gao. An AI platform for vascular and fibrosis analysis of pathology images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6592.
Abstract 6598: The development of a tumor-agnostic liquid biopsy assay for minimal residual disease detection and monitoring in cancers
Authors: Bonora Giancarlo , Dong Hang , Dai Chao , Xiang Binggang , Gould Billie , Zhen Tiantian , Mo Wei , Wang Xiaohong , Zhou Kemin , Jia Shidong , Luo Shujun , Du Pan 
Published: April 2023

Abstract
Purpose
Non-invasive liquid biopsy (LBx) based assays hold great promise for early cancer diagnosis and disease progression monitoring. Personalized baseline tissue-informed minimal residual disease (MRD) monitoring exhibits a particularly high detection sensitivity in many studies, however, baseline samples (especially tissue biopsies) are often difficult to acquire in a clinical setting, and the personalized panel design and tracking creates operation complexities.
Methods
We developed PredicineALERTTM, a baseline-agnostic MRD LBx assay that measures methylation and mutational variants associated with cancers. At its core lies the PredicineEPICTM DNA methylation assay with the advantage of low DNA damage and low input amount. Tumor burden is assessed by detecting abnormally methylated DNA fragments with high sensitivity using the Predicine DeepSea bioinformatics analysis pipeline. PredicineALERTTM provides integrated methylation and mutational profiling, as well as copy number variation (CNV) profiling.
Results
The PredicineALERTTM assay was tested using longitudinal LBx samples (blood, urine, CSF) from patients with mCRPC, CRC, NSCLC, breast, liver, kidney, prostate, and bladder cancers. The PredicineALERTTM assay demonstrates highly-sensitive MRD detection and quatification capability (LOD &lt; 0.01%) using 2.5 - 15ng input cfDNA. It has the ability to identify unique cancer biomarker signatures, and robustly detect MRD ctDNA dynamics during treatment. By leveraging genome-wide fragment-level DNA methylation, PredicineALERTTM measures molecular response and MRD in targeted therapy, immunotherapy and chemotherapy. A strong concordance was observed in the pattern of tumor burden as ascertained by CNV and methylation analyses, respectively.
Conclusion
We developed PredicinceALERTTM, a baseline agnostic, multidimensional MRD LBx assay without the need for baseline samples and personalized panel design. It integrates DNA methylation, mutation, and copy number changes for detecting MRD from genome-scale data without relying on target selection before library generation.
Citation Format: Giancarlo Bonora, Hang Dong, Chao Dai, Binggang Xiang, Billie Gould, Tiantian Zhen, Wei Mo, Xiaohong Wang, Kemin Zhou, Shidong Jia, Shujun Luo, Pan Du. The development of a tumor-agnostic liquid biopsy assay for minimal residual disease detection and monitoring in cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6598.
Abstract 6607: Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision oncology
Authors: Goodman Kelli , Showalter Megan R. , Evans Anne M. , Mitchell Matthew W. , Sarangarajan Rangaprasad 
Published: April 2023

Abstract
The COVID19 pandemic accelerated opportunities for innovation within the decentralization process of clinical trials with opportunities for implementation of patient-centric workflows for efficiency and cost-reduction. Decentralized sample collection, particularly whole blood using dried blood spots (DBS) provides the ideal mechanism for patient driven sample collection with ease of access to sample generation, drug level assessments and metabolomic prMegofiling, providing longitudinal real-time measure of drug specific pharmacodynamic readout for safety and efficacy. In this study, we report the development of a protocol for the capture and comprehensive profiling of metabolomics using dried blood spots from a cohort of 49 healthy volunteer donors. Using liquid chromatography combined with mass spectrometric (UPLC-MS/MS) methods an untargeted metabolomic approach resulted in the identification of &gt;800 biochemicals of which a significant subset was found to be presented in corresponding matched plasma (from whole blood) samples. The biochemicals identified from the DBS samples included metabolites that were part of the lipid, amino acid, nucleotide, peptide, cofactors, carbohydrate and energy super pathways. A significant number of metabolites identified in the DBS samples were xenobiotics including those representing the biotransformation products of drugs. The overall metabolite profiles were analyzed for precision and accuracy of measure, variability in performance and dynamic range to establish benchmarks for evaluation. An additional cohort with a longitudinal sampling as part of the protocol provided the reproducibility of the analytic method for inter-day variability of metabolite performance over time. Although metabolomic profiles varied between individuals from a population perspective, there was minimal variation observed within individuals when samples were profiled longitudinally over several weeks. Thus, the protocols for DBS collection and the corresponding capture of a large set of metabolites with reproducible performance provides an opportunity for its implementation in oncological clinical trials as part of a de-centralized clinical trial solution.
Citation Format: Kelli Goodman, Megan R. Showalter, Anne M. Evans, Matthew W. Mitchell, Rangaprasad Sarangarajan. Dried blood spot (DBS) sample analysis for drug and metabolomic profiling in oncology clinical trials: Cost-effective decentralized sampling modality for precision oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6607.
Abstract 795: T-cell mediated response to emerging COVID-19 strains in patients with cancer studied via deep learning
Authors: Lyudovyk Olga , Elhanati Yuval , Streltsov Artem , Morris Quaid , Vardhana Santosha , Greenbaum Benjamin 
Published: April 2023

Abstract
Cancer patients, particularly those receiving B cell-depleting therapy for lymphoid malignancies, are at risk of prolonged SARS-CoV-2 infection, poorer clinical outcomes, and delayed initiation or disruption of cancer-directed therapy (Lee at al., 2022, Clark et al., 2021). We first studied T-cell mediated response to the Wuhan strain of SARS-CoV-2 in a cohort of 69 patients with hematologic and solid cancers, including 18 patients who received prior B-cell depleting therapy. Patients with prolonged COVID-19 clearance, defined by a positive PCR test for longer than 30 days, had a broad but poorly converged CD8+ dominant response and a lacking CD4+ response. To conduct this analysis, we performed bulk T-cell receptor (TCR) sequencing of 121 blood samples and tracked over time TCR repertoire statistics such as clonality, convergence, breadth, and depth of COVID-19-associated TCRs during the active and convalescent periods of COVID-19 infection. These SARS-CoV-2-associated TCRs were identified leveraging immunoSEQ T-MAP database (Snyder et al., 2020), a set of TCR sequences derived from COVID-19 patients and experimentally identified as responsive to MHC Class I and II epitopes from the Wuhan SARS-CoV-2 strain using the multiplex identification of TCR antigen assay (Klinger et al., 2015). To extend our TCR repertoire analysis to other SARS-CoV-2 variants, including Omicron, we developed a deep learning (DL) method to predict TCR specificities for new SARS-CoV-2 epitopes. This DL approach also permits the identification of SARS-CoV2-responsive TCRs private to an individual. Combining this DL approach with our TCR statistics methodology, we studied the dynamics of T-cell response to COVID-19 vaccinations in a cohort of 50 patients with cancer and analyzed TCR repertoire characteristics associated with different degrees of COVID-19 severity in a cohort of 42 cancer patients who contracted the Omicron. Understanding cellular response to novel infections is critical for patient care in the context of cancer, and our novel DL-based approach can leverage existing datasets to analyze and track response to emerging viral strains.
Citation Format: Olga Lyudovyk, Yuval Elhanati, Artem Streltsov, Quaid Morris, Santosha Vardhana, Benjamin Greenbaum. T-cell mediated response to emerging COVID-19 strains in patients with cancer studied via deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 795.