bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 129: Effect of punicic acid on MCF7 breast cancer cells
Authors: Gbayisomore Oluwafemi , Klausner Hannah , Phelan Shelley A. 
Published: June 2022

Abstract
The pomegranate fruit has long been recognized for its health benefits in a wide range of chronic diseases. Components of pomegranate seed extracts (PSOs) have been shown to have antioxidant, anti-glycemic, and antimicrobial activity, and recent research has demonstrated that PSOs can inhibit the growth of select cancers in vitro. One of the main components of PSO is punicic acid, an omega-5 fatty acid that is capable of inhibiting breast and prostate cancer cell proliferation, although the mechanisms of action are not yet known. In order to further understand its potential anti-cancer properties, we investigated the effect of punicic acid on proliferation and viability of human MCF7 breast cancer cells. Cells were treated with various concentrations of punicic acid (between 10 and 100ug/ml) for up to 72 hours, and various endpoints were measured including cell proliferation, cytotoxicity, and apoptosis. We found that all doses led to a significant reduction in cell viability based on an MTS assay. We also found a dose-dependent effect of punicic acid on cytotoxicity, as measured by an LDH release assay. Cell death was confirmed to be, at least in part, due to apoptosis, as detected by Annexin V and propidium iodide fluorescence. While 10 ug/ml punicic acid induced measurable cell death by 48 hours, higher concentrations were toxic to cells within the first 24 hours of treatment. Since many of the peroxiredoxin (Prdx) family of antioxidant proteins are known to involved in cancer cell survival, and our lab previously demonstrated their regulation in MCF7 cells, we examined the effect of punicic acid on Prdx expression. We found members of this gene family to be significantly elevated within 24 hours of punicic acid treatment. Altogether, our data definitively demonstrates anti-cancer properties of punicic acid, as well as its ability to regulate antioxidant gene expression in these cells. This research has important implications in the field of natural products as therapeutic options for cancer treatment, as opposed to conventional chemotherapy.
Citation Format: Oluwafemi Gbayisomore, Hannah Klausner, Shelley A. Phelan. Effect of punicic acid on MCF7 breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 129.
Abstract 130: Pharmacological effects of selective xCT inhibition in ARID1A mutated cancer models
Authors: Henry Christophe , Péron Philippe , Blanchet Anne-Marie , Genevois-Borella Arielle , Trellu Marc , Bourges Dorothée , Lienard Philippe , Basset Alexandra , Jouannot Erwan , Philippo Christophe , Debussche Laurent , Moll Jürgen 
Published: June 2022

Abstract
xCT is a cystine/glutamate antiporter that exports intracellular glutamate for extracellular cystine. In the intracellular space, cystine is converted into cysteine which is subsequently used for glutathione (GSH) synthesis (a major antioxidant species). ARID1A is part of the SWI-SNF remodeling complex that binds on the xCT promoter and as such controls its gene expression. ARID1A deficiency which is highly prevalent in many cancers results in downregulation of xCT, impaired GSH biosynthesis and subsequent ROS induction, raising potential rationale to target xCT in ARID1A deficient cancers. By using a selective nanomolar range xCT inhibitor, we first showed that cell lines deficient for ARID1A were significantly more sensitive to the inhibition of xCT. Effects on proliferation could be reversed by N-acetylcysteine supplementation in the culture medium. In vivo, the xCT inhibitor confirmed its drug-like properties showing significant target engagement in an ARID1A deficient ovarian cell line xenograft model together with good PK and tolerability profiles. Altogether these studies have provided evidence that a specific drug-like inhibitor of xCT can be developed. This proprietary compound was used to confirm that in vitro the deficiency of ARID1A in ovarian cancer predicts sensitivity to xCT inhibition. Further in vivo pharmacological studies are required to confirm a specific molecular context predicting sensitivity towards xCT inhibition.
Citation Format: Christophe Henry, Philippe Péron, Anne-Marie Blanchet, Arielle Genevois-Borella, Marc Trellu, Dorothée Bourges, Philippe Lienard, Alexandra Basset, Erwan Jouannot, Christophe Philippo, Laurent Debussche, Jürgen Moll. Pharmacological effects of selective xCT inhibition in ARID1A mutated cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 130.
Abstract 1315: Tumor necrosis factor related apoptosis inducing ligand fosters myeloid derived suppressor cell mediated tumor immune evasion in cholangiocarcinoma
Authors: Loeuillard Emilien , Yang Jingchun , Dong Haidong , Gores Gregory J. , Ilyas Sumera I. 
Published: June 2022

Abstract
Background and Aims: Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is predominantly expressed on immune cells. Although TRAIL biology has garnered considerable attention as a potential anti-cancer strategy, TRAIL agonists have had very limited anti-cancer activity in humans. TRAIL signaling can attenuate the T lymphocyte response. However, this potential immunosuppressive function of TRAIL has not been examined in cancer biology. Cholangiocarcinoma (CCA), a highly lethal biliary tract cancer, has a dense immunosuppressive microenvironment. Accordingly, CCA provides a model to examine the potential immune regulatory function of TRAIL in cancer biology.
Methods: Using a syngeneic, orthotopic murine model of CCA (PMID: 29464042), murine CCA cells (SB cells) that express both Trail and Trail receptor (Tr) were implanted into livers of WT and Tr-/- mice. Hence, in this model the host immune cells express Trail but not the receptor; therefore, they would be capable of inducing TRAIL-mediated apoptosis in CCA cells but would be resistant to TRAIL-mediated immunosuppression. After 4 weeks of tumor growth, mice were sacrificed, and tumors were characterized using flow cytometry.
Results: We observed that Tr-/- mice had a significant reduction in tumor burden compared to WT mice. Moreover, tumor bearing Tr-/- mice had a significant increase in cytotoxic T lymphocytes (CTLs) and enhanced CTL effector function. Myeloid-derived suppressor cells (MDSCs) were significantly decreased in Tr-/- tumors compared to WT tumors. Furthermore, implantation of SB cells devoid of Trail (SB-Trail-/-) into WT mice resulted in a significant reduction in tumor burden and MDSC infiltration. In vitro functional studies employing SB cells deficient in Tr (SB-Tr-/-) and MDSCs were carried out. There was a significant reduction in proliferation and immunosuppressive function of MDSCs when cocultured with SB-Tr-/- compared to SB cells. These results indicate that TRAIL-TR fosters MDSC growth and immunosuppressive function.
In conclusion, we have demonstrated that Tr-/- mice have a significant reduction in CCA tumor burden and MDSC infiltration. Consequently, Tr-/- tumors have enhanced CTL infiltration and function. These data suggest that the TRAIL-TR system mediates tumors immune evasion via MDSCs, and direct targeting of TRAIL on CCA cells is a potential anti-tumor strategy.
Citation Format: Emilien Loeuillard, Jingchun Yang, Haidong Dong, Gregory J. Gores, Sumera I. Ilyas. Tumor necrosis factor related apoptosis inducing ligand fosters myeloid derived suppressor cell mediated tumor immune evasion in cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1315.
Abstract 1344: Immune transcriptional profiling in a large animal model of histiocytic sarcoma reveals putative drivers and tumor suppressors
Authors: Lenz Jennifer A. , Assenmacher Charles-Antoine , Radaelli Enrico , Atherton Matthew J. 
Published: June 2022

Abstract
Histiocytic sarcoma (HS) is a rare, yet lethal malignancy with a median overall survival of six months and no universally agreed standard of care therapy. Due to the paucity of human cases, there is a drive to develop model systems to improve our understanding of the pathology underlying this disease and screen new treatment strategies. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Our previous studies revealed a spectrum of hot and cold immune tumor microenvironments (TME) based on tumor infiltrating lymphocyte (TIL) quantification in 18 canine and 5 human HS cases. In dogs, increased TIL densities were positively associated with longer survival times. Despite this association, the disease course of HS in our veterinary patient cohort was nearly uniformly fatal. To evaluate for potential inhibitors of T cell immunity in the TME and identify putative drivers and suppressors of HS, we performed immune transcription profiling. Tumors were selected from 3 short-lived cases of splenic HS that were sparsely infiltrated with TIL and 3 long-lived cases of pulmonary HS that were T cell inflamed. Tumors were compared to corresponding grossly healthy splenic and lung tissues collected from 3 dogs without neoplasia undergoing routine post-mortem examination. RNA was extracted from formalin-fixed paraffin embedded tissues and immune transcription profiling was performed using the NanoString nCounter Canine IO Panel. Analyses of all tumors compared to normal tissues, and subset analyses of tissues stratified based on tissue origin site, revealed enrichment of ITGAX (CD11c) expression in the HS tumor samples consistent with histiocytic origin. In each subset analysis, SPP1 (osteopontin) was highly expressed in HS tumors compared with normal tissues. Osteopontin has been shown to be protumorigenic in a variety of cancers, is a potent chemokine for macrophages, and can suppress T cell activation through ligation of CD44, thus acting as a T cell checkpoint. Additionally, we found decreased expression of TXNIP in HS tumors compared to healthy tissues. TXNIP is an established tumor suppressor gene in various tumor types, including acute myeloid leukemia. Future studies will interrogate the functional implications of these transcriptional changes with the aim of developing novel therapeutic strategies for HS in both species.
Citation Format: Jennifer A. Lenz, Charles-Antoine Assenmacher, Enrico Radaelli, Matthew J. Atherton. Immune transcriptional profiling in a large animal model of histiocytic sarcoma reveals putative drivers and tumor suppressors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1344.
Abstract 1366: A novel stem cell memory T cell subpopulation intermediate to canonical stem cell memory and central memory T cells in human cancer
Authors: Powell Daniel J. 
Published: June 2022

Abstract
Stem memory T cells (Tscm) are integral for effective immunotherapy and antitumor responses, but little is known about Tscm immunobiology in solid human tumors. Here we identify self-renewing and multipotent Tscm tumor-infiltrating lymphocytes (TILs) in human cancer and present a novel Tscm subset which expresses CD45RO, is derived from CD45RO- Tscm T cells, and is capable of self-renewal and multipotency. From the analysis of CD45RO+ Tscm differentiation, phenotyping, gene expression, and the broader TCR repertoire, we find that CD45RO+ Tscm cells are hierarchically positioned in between canonical CD45RO- Tscm cells and central memory T cells. Notably, CD45RO+ Tscm cells exhibit a gene expression profile consistent with effector capabilities and a tumor-specific phenotype that is more similar to T cells associated with successful immunotherapy than canonical Tscm. Thus, we describe a novel Tscm subset in human cancer which has distinct phenotypic, transcriptional, and effector-like attributes that position it as an attractive subset for future basic and clinical research in the setting of cancer immunotherapy.
Citation Format: Daniel J. Powell. A novel stem cell memory T cell subpopulation intermediate to canonical stem cell memory and central memory T cells in human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1366.
Abstract 1370: Targeting LSD1 rescues MHC-I antigen presentation in small cell lung cancer
Authors: Nguyen Minh N. , Taniguchi Hirokazu , Chow Andrew , Zhan Yingqian A. , Sen Triparna , Rudin Charles M. 
Published: June 2022

Abstract
Purpose: Small cell lung cancer (SCLC) is a highly aggressive cancer with early primary resistance and modest clinical benefit to immune checkpoint blockade (ICB). Mutation or transcriptional repression of the major histocompatibility complex class I (MHC-I) is a key mechanism driving resistance to T cell-based therapies. Lysine Demethylase 1 (LSD1) regulates gene expression through modulating mono- and di- methylated lysine 4 and 9 of histone H3. LSD1 is a therapeutic target of interests in SCLC due to its oncogenic requirement for tumor growth, and there has been growing evidence pointing to LSD1 as a repressor of tumor-intrinsic immunogenicity. Here investigated the role of LSD1 as a transcriptional regulator of antigen presentation in SCLC.
Method: To perturb LSD1 function, we employed the pharmacological inhibitor ORY-1001 and shRNA-mediated knockdown. We then assessed changes in MHC-I expression on SCLC cell lines by flow cytometry and western blot. To analyze transcriptional changes following LSD1 inhibition, we performed RNA-seq on SCLC cells pre- and post-treatment with ORY-1001. To observe for antigen-specific T cell killing, we engineered SCLC cells to express endogenous antigens and co-cultured these cells with primary cognate CD8+ T cells. Finally, we treated genetically engineered mouse model (GEMM)-derived tumors on immunocompetent syngeneic mice with ORY-1001 with or without anti-PD-L1 blockade to assess for anti-tumor effects.
Results: We discovered a significant and strong negative correlation between expression of LSD1 and genes encoding the MHC-I antigen presentation pathway. Inhibition of LSD1 induces expression of MHC-I genes and restores expression of genes encoding the antigen presentation machinery. Perturbation of LSD1 further activates interferon signaling and interferon-inducible expression of NLRC5, a well-characterized transcriptional activator of MHC-I genes. We further showed that targeting LSD1 sensitizes SCLC cells to MHC-I-restricted T cell-dependent cytolysis and enhances ICB efficacy in refractory SCLC tumors.
Conclusion: Our data define a role for LSD1 as a potent negative regulator of MHC-I-mediated antigen presentation and provide rationale for the use of LSD1 inhibitors to augment response to immunotherapy in SCLC.
Citation Format: Minh N. Nguyen, Hirokazu Taniguchi, Andrew Chow, Yingqian A. Zhan, Triparna Sen, Charles M. Rudin. Targeting LSD1 rescues MHC-I antigen presentation in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1370.
Abstract 1373: PeptidePCR: Direct identification of cancer vaccine targets from scant clinical samples
Authors: Ramarathinam Sri H. , Faridi Pouya , Peng Angela , Szeto Pacman , Wong Nicholas C. , Behren Andreas , Shackleton Mark , Purcell Anthony W. 
Published: June 2022

Abstract
Background: Peptides presented by Human Leukocyte antigen (HLA) class I and II molecules form an important component of the adaptive immune response against tumors. Identifying HLA-bound peptides is therefore crucial to understand the specificity of T cell responses in cancer. Due to sample limitations, it is often difficult or impossible to confirm epitope presentation in clinical biopsy material. To develop truly personal medicine, target epitopes need to be directly identified or validated in patient tumors at the peptide antigen level.
Methodology: We have developed a microscale HLA immunoprecipitation protocol which when combined with a tandem mass tag (TMT)-based barcoding approach was able to identify HLA-bound peptides. HLA-complexes were affinity purified from either cultured cells, patient-derived xenograft or melanoma biopsies and the peptide cargo was tagged using TMT barcodes and analyzed using high-resolution mass spectrometry. Like primers in PCR, the carrier peptides and multiplexing of samples amplifies the signal enabling sensitive detection.
Results: By using this strategy, we identified HLA-bound peptides from as few as ~1000 cultured cells. We demonstrate the clinical utility of this approach by confirming the presentation of around 1000 peptides from a challenging melanoma biopsy (~1-20mg in total), including 11 well-known T-cell response-inducing epitopes and other potential epitopes derived from Melanoma-associated antigens and neoantigens.
Conclusion: This strategy will be useful for studying peptidome subsets in other clinical samples where the amount of tissue available via sampling is limiting, including biopsies taken for autoimmune diseases and infections, or to sample rare cell types in tissue/cell samples, such as different antigen-presenting cell subsets. The approach can directly isolate antigens that are already presented by HLA molecules, thereby increasing the precision of personalized approaches to cancer treatment with less than 1-week turnaround times.
Citation Format: Sri H. Ramarathinam, Pouya Faridi, Angela Peng, Pacman Szeto, Nicholas C. Wong, Andreas Behren, Mark Shackleton, Anthony W. Purcell. PeptidePCR: Direct identification of cancer vaccine targets from scant clinical samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1373.
Abstract 1421: Non-invasive early detection of pancreatic ductal adenocarcinoma using methylation signatures in circulating tumor DNA
Authors: Gore Athurva J. , Dang Justin , Fung Alan , Xie Bin , Liu Rui 
Published: June 2022

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) has a low overall survival rate primarily due to late onset of symptoms and rapid progression. Early symptoms, which include abdominal and back pain, diarrhea, weight loss, and jaundice are non-specific for PDAC and may be associated with other gastrointestinal diseases. PDAC lacks reliable and accurate tests for early detection. We aimed to discover biomarkers carrying a PDAC-specific DNA methylation signature in blood cell-free DNA, and to develop and validate a non-invasive test for PDAC detection.
Methods: Reduced representative bisulfite sequencing (RRBS) was previously performed on tissue and plasma samples from PDAC patients and healthy individuals to identify PDAC-specific methylation markers. These markers were combined with previously reported cancer methylation markers for a second round of marker screening. The resulting markers were utilized to develop a targeted methylation sequencing assay for plasma DNA, designated as PDACatch. The PDACatch assay was validated on an independent sample set to demonstrate its efficacy for pancreatic cancer methylation signature detection.
Results: The PDACatch assay was performed on 91 PDAC plasma and 84 healthy plasma samples obtained from commercial biobanks. In this independent verification sample set, the PandaX assay predicted PDAC from healthy with AUC of 0.91; accuracy remained high for classification of both stage I and early-stage (I/IIa) samples.
Conclusion: The PDACatch assay, a ctDNA methylation based blood test, achieved a high accuracy for detecting PDAC at early stages, indicating its potential in screening effectiveness.
Citation Format: Athurva J. Gore, Justin Dang, Alan Fung, Bin Xie, Rui Liu. Non-invasive early detection of pancreatic ductal adenocarcinoma using methylation signatures in circulating tumor DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1421.
Abstract 1443: Environmental heavy metal toxicity and mammographic breast density in a Mississippi Delta southern state
Authors: Fine Bobbie Dean , Stahr Shelbie , Rogers Lora J. , Runnells Gail A. , Chiang Tung-Chin , Su Lihchyun J. 
Published: June 2022

Abstract
Importance: Increased mammographic density (MD) is a strong independent risk factor for breast carcinoma. Ubiquitous environmental heavy metal (HM) exposure/toxicity appears pro-carcinogenic in several human cancers. However, studies in the current scientific literature have not elucidated specific connections between HM exposure and mammographically detected increases in breast density.
Objective: To determine whether increases in heavy metals (ie, chromium, arsenic and cadmium) measured in urine as a biomarker for long-term exposure, associate with increased MD in a female study cohort in Arkansas.
Design, Setting, Participants: One hundred thirty-nine participants in the Arkansas Rural Community Health (ARCH) study cohort, recruited through a mobile mammography unit at baseline, were included in this pilot study. Demographic/health history questionnaire data, urine, blood and saliva samples and incident mammograms classified by BI-RADS were ascertained after informed consent. Study protocol was approved by the Institutional Review Board at the University of Arkansas for Medical Sciences (UAMS).
Main Outcome and Measures: Urinary chromium, arsenic and cadmium levels were determined using inductively coupled plasma mass spectrometry. The concentrations of HM were adjusted for urinary creatinine and specific gravity and the results categorized into tertiles. Multivariable logistic regression models were used to evaluate the association between HM exposure and MD. Association of both continuous and categorical variables were examined. Confounding variables in the multivariable models including age, race, BMI, age at menarche and smoking history were determined by a priori knowledge and statistical assessment.
Results: Odds ratios (OR) and 95% confidence intervals (CI) for the association between each tertile of HM exposure and MD were used for the assessment. For the unadjusted model, increasing ORs for MD were noted with increased levels of both Chromium and Arsenic exposure. Increased ORs for MD were observed with increased levels of Chromium, Arsenic and Cadmium exposure in the multivariable adjusted model. However, none of these associations demonstrated statistical significance in this limited pilot study.
Conclusion: Positive associations between HM exposure and MD were noted after adjusting for age, sex, BMI, age at menarche and smoking history in this pilot study. However, the association did not reach statistical significance at α = 0.05.
Citation Format: Bobbie Dean Fine, Shelbie Stahr, Lora J. Rogers, Gail A. Runnells, Tung-Chin Chiang, Lihchyun J. Su. Environmental heavy metal toxicity and mammographic breast density in a Mississippi Delta southern state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1443.