bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3085: Role of amino acid sequences within the N terminal domain in regulating AF1-mediated glucocorticoid receptor activity
Authors: Khan Shagufta H. , Kumar Raj 
Published: June 2023

Abstract
The steroid hormone receptors (SHRs) play an important role in many physiological and pathological processes including endocrine cancers. However, the precise mechanisms by which these SHRs pass signals from a hormone to control gene expression remain a central unresolved problem, which has limited SHRs therapeutic utilities in a cell/tissue specific manner. Role of the activation function-1 (AF1) in this process is of immense importance as it provides platforms for interactions of specific co-regulatory proteins, and thereby dictates the final outcome SHR-regulated target gene expression. The AF1 located in the N-terminal domain (NTD) plays a critical role in regulating cell/tissue-specific effects of SHRs. However, the exact mechanism of this action is not known. It has been suggested that cell/tissue-specific activities of SHRs may be due to AF1 conformations and subsequent coactivator interactions. The SHRs’ NTD/AF1 has been reported to exist in an intrinsically disorder conformation and undergoes disorder-order transition through intra- and inter- molecular allosteric regulations. In the study, we tested whether the flanking sequences around AF1 affect glucocorticoid receptor (GR) activity due, in part, to conformational changes in otherwise ID AF1 that can facilitate its interaction with critical coregulatory proteins such as TATA Box-Binding Protein (TBP) and steroid receptor coactivator-1 (SRC-1). Using biophysical techniques, we found that placing AF1 immediately upstream from the DNA binding domain (DBD) results into acquisition of a relatively ordered conformation in GR AF1. Further analyses revealed that removing amino acid sequences (1-76) prior to AF1 or removal of amino acids (263-420) between AF1 and DBD differentially regulates AF1-mediated GR activity. The results from this study may provide a potential mechanism for cell-dependent differing GR activities as well as other SHRs and thereby, our results may provide additional SHR selectivity needed to target cell-tissue specific gene regulations in current endocrine-based therapies.
Citation Format: Shagufta H. Khan, Raj Kumar. Role of amino acid sequences within the N terminal domain in regulating AF1-mediated glucocorticoid receptor activity [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 3085.
Abstract 3328: Using Luminex approach to develop a panel of anti-TAA autoantibodies for the detection of prostate cancer
Authors: Qiu Cuipeng , Wang Xiao , Batson Serina , Francia Giulio , Zhang Jian-Ying 
Published: June 2023

Abstract
Autoantibodies to tumor-associated antigens (TAAs) have been demonstrated as reporters in early carcinogenesis. Luminex technology enables the development of simultaneous detection of multiple autoantibodies. This study aimed to use Luminex technology to evaluate and develop an optimal panel for the detection of prostate cancer (PCa) based on autoantibodies to fourteen TAAs (p53, p16, IMP2, IMP3, SOX2, BIRC5, HIF1-α, HSP60, ENO1, CTAG1B, MUC1, Her2, GAL1, and GAL3) associated with cancers. A total of 163 samples including 91 PCa sera and 72 normal control sera were screened to evaluate the expression of fourteen autoantibodies by multiple autoantibody bead panel. Except for autoantibodies to Her2 and IMP3, twelve autoantibodies showed significantly high frequencies ranging from 19.8% to 51.6% in the PCa group at 95.8% specificity for normal controls. The area under the curve (AUC) of these twelve autoantibodies ranged from 0.609 to 0.868. After logistic regression modeling and leave-one-out cross-validation, an optimal panel with the combination of three autoantibodies to p16, IMP2, and HSP60 was developed, achieving an AUC of 0.909 with 71.4% sensitivity and 95.8% specificity. Autoantibody to HSP60 exhibiting the best performance with an AUC of 0.868 in the autoantibody bead panel was further validated by Enzyme-linked immunosorbent assay (ELISA) with a larger size sample containing 200 PCa sera and 137 normal control sera, it also showed an AUC of 0.848 to identify PCa from normal controls. Therefore, the autoantibody bead panel showed similar results to ELISA. In summary, we developed an optimal autoantibody bead-based panel for the detection of PCa. It could be used as a high throughput tool to facilitate Pca detection.
Citation Format: Cuipeng Qiu, Xiao Wang, Serina Batson, Giulio Francia, Jian-Ying Zhang. Using Luminex approach to develop a panel of anti-TAA autoantibodies for the detection of prostate cancer [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 3328.
Abstract 3384: Evaluation of a tumor informed MRD assay with contrived breast cancer samples
Authors: Russell Hugh , LaBrousse Paul , Stetson Daniel , Jones Greg , Marsico Giovanni , Forshew Tim , McEwen Robert , De Bruin Elza , Abbosh Christopher , Hodgson Darren , Dougherty Brian , Hadfield James , Barrett Carl 
Published: June 2023

Abstract
The non-invasive detection of circulating tumor DNA (ctDNA) from plasma has been shown to have clinical value for detection of minimal residual disease (MRD), emergence of resistance, and predicting treatment response. The sensitive detection of MRD following curative treatment allows for the identification of patients destined to recur. Higher assay sensitivities enable the longest lead times to clinical recurrence. Evaluations using several contrived pan-cancer samples have shown that the Inivata RaDaR tumor-informed personalized assay has a high sensitivity to detect ctDNA. The tumor-informed analysis utilizes sequencing of the tumor tissue to identify up to 48 clonal somatic variants, which are selected to generate a personalized panel to track the variants in patient plasma. To evaluate this technology in a disease specific manner, we generated a set of contrived plasma samples from commercial breast cancer patients and healthy individuals. The biological materials allowed us to generate a plasma sample with defined range of tumor content between 0.2 and 0.001% variant allele fraction (VAF). The sample dilutions were intended to recapitulate challenging cell-free DNA inputs that can be encountered in a clinical setting (median input: 5.76 ng [range 0.22 to 103.73]. Through our pan-cancer and breast cancer evaluations, we were able generate both sensitivity metrics along with a small limit of detection (LOD) study. The assay successfully detected tumor fractions in samples tested at 1X and 1.5X of the established LOD95% of 0.0011% VAF. RaDaR was able to detect the majority of MRD+ samples at 0.5X LOD. We will present data showing the level of sensitivity based on using both 2000 and 20000 genomic equivalents. The RaDaR assay showed high sensitivity for pan-cancer as well as ER+ breast cancer, which is known to have a low TMB compared to other subtypes. In this albeit small LoD study the Inivata assay was highly sensitive for the detection of ctDNA which is imperative to confidently detect ctDNA in advance of overt clinical recurrence.
Citation Format: Hugh Russell, Paul LaBrousse, Daniel Stetson, Greg Jones, Giovanni Marsico, Tim Forshew, Robert McEwen, Elza De Bruin, Christopher Abbosh, Darren Hodgson, Brian Dougherty, James Hadfield, Carl Barrett. Evaluation of a tumor informed MRD assay with contrived breast cancer samples [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 3384.
Abstract 339: Exploring the roles of GSDMD in mammary tumorigenesis
Authors: Zhang Derek Yisen 
Published: June 2023

Abstract
Breast cancer (BC) is the most frequently diagnosed cancer worldwide, with an ever-increasing incidence rate. While screening and treatment methods have improved markedly over the last three decades, BC remains the leading cause of malignant death in women annually. Therefore, there is an urgent need to identify new biomarkers and therapeutic targets for BC. Recently, dysregulated gasdermin D (GSDMD), a central player of inflammation-induced cell death called pyroptosis, has been shown to be implicated in cancer. However, it is unclear whether GSDMD plays important roles in BC. In addition, the molecular mechanism underlying GSDMD-involved tumorigenesis remains unknown. Here, we discovered that GSDMD is significantly upregulated in BC. We have shown that overexpression or knockout of GSDMD increases or decreases BC cell proliferation, respectively. In addition, we have identified and validated several novel GSDMD-interacting proteins that play important roles in breast cancer. These present findings will not only shed light on the roles of GSDMD in BC tumorigenesis but also provide new preclinical data for future successful treatments of BC patients.
Citation Format: Derek Yisen Zhang. Exploring the roles of GSDMD in mammary tumorigenesis [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 339.
Abstract 380: BaF3-BTK engineering cell lines as a useful platform for novel BTK inhibitor discovery
Authors: Wang Guoqian , Chen Hongling , Wang Yu , Xu Jingxiao , Zhou Lin , Tang Yao , Ning Jinying , Hao Feng 
Published: June 2023

Abstract
Introduction: Bruton's tyrosine Kinase (Btk) plays an essential role in BCR signaling and has been a hot new target in molecular targeted therapy in the past few years, led by the clinical success of ibrutinib and acalabrutinib, two first approved BTK inhibitors, that greatly improved the outcome of patients with relapsed chronic lymphocytic leukemia (CLL). Currently, there are 5 approved BTK inhibitors including additionally zanubrutinib, orelabrutinib and velexbru. Up to 24 BTK inhibitors are under active clinical evaluation as antineoplastic drugs against chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B-cell malignancies and mantle cell lymphoma (MCL) in different countries. However, the acquired resistance due to the C481S mutation in BTK remains an essential challenge to improve the poor prognosis of the patient. Subsequently, several next-generation BTK inhibitors are under clinical evaluation targeting the BTK-C481S mutation, such as LOXO-305, a highly selective and non-covalent BTK inhibitor which potently inhibits the cellular activity of BTK C481S/T/R mutations.
Methods: Our group has generated 9 Ba/F3-BTK engineering cell lines as useful cell line and xenograft models for novel BTK inhibitor discovery and development. They harbor wild type BTK or ibrutinib resistance BTK mutations such as the C481S and C481S-double mutations, and the T474M/I mutations. Moreover, we generated Ba/F3-ETV6-BTK-F517L and Ba/F3-ETV6-BTK-C481S-F517L cell lines using a dose-escalation method after treating cells with a mutagenic agent. The BTK-F517L mutation is highly resistant to both ibrutinib and LOXO-305 treatment. Crystal structure analysis and 3D modeling revealed that the F517L mutation may affect the conformation of the BTK binding pocket to ibrutinib, indicating novel BTK inhibitors may be needed to overcome this resistance mutation.
Conclusion: The Ba/F3-BTK engineering cell lines can be a useful tool to develop and evaluate next-generation BTK inhibitors and to explore new acquired resistance BTK mutations.
Citation Format: Guoqian Wang, Hongling Chen, Yu Wang, Jingxiao Xu, Lin Zhou, Yao Tang, Jinying Ning, Feng Hao. BaF3-BTK engineering cell lines as a useful platform for novel BTK inhibitor discovery [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 380.
Abstract 3801: Identification of circular RNAs associated with the ferroptosis of pancreatic cancer cells
Authors: Paladines Jessica Jazmin Pena , Wang Shao Weng , Wong Chi Hin , Chen Yang Chao 
Published: June 2023

Abstract
The five-year survival rate for pancreatic cancer patients is significantly low which is predominately due to the lack of early-detection biomarkers, and poor response to currently available treatments that include drug resistance development. Recent studies suggest cancer cells can be highly sensitive to a newly defined type of cell death, ferroptosis, which is related to the development of resistance to standard chemotherapy drugs for pancreatic cancer such as gemcitabine and 5-Fluorouracil. However, the role of circular RNAs (circRNAs) in ferroptosis remains largely unexplored. Hence, this project aims to identify circRNAs in ferroptosis to uncover further components and mechanisms, and potentially provide specific effective targets for anticancer therapies. To achieve this, different ferroptosis inducers were tested, where the cystine-depletion method demonstrated higher efficiency based on cell viability and ferroptosis markers such as iron and lipid peroxidation levels. This method was used to induce ferroptosis for 24 hours in pancreatic cancer cells for subsequent circRNA sequencing, and to establish a ferroptosis-resistant cell line. From the sequencing data, 31 differentially expressed (DE) circRNAs were obtained, and eight were selected for further validation. Three circRNAs; circPPP2R2B, circNDUFAB1, and circNLN, showed consistent differential expression in ferroptosis non-resistant (downregulated) and resistant (upregulated) cells after cystine-depletion treatment. The knockdown of these circRNAs decreased the viability, invasion, migration, and colony formation ability of PDAC cells. Simultaneously, lipid peroxidation and intracellular iron levels, which are ferroptosis markers, were increased. Additionally, bioinformatic analysis of these circRNAs demonstrated their possible interaction with proteins and miRNAs with reported ferroptosis-related functions. In summary, these findings suggest that circPPP2R2B, circNDUFAB1, and circNLN may be critically involved in PDAC progression and the evasion of ferroptosis which supports the further investigation of their oncogenic and ferroptosis-related action mechanism to propose a potential target for anticancer therapies.
Citation Format: Jessica Jazmin Pena Paladines, Shao Weng Wang, Chi Hin Wong, Yang Chao Chen. Identification of circular RNAs associated with the ferroptosis of pancreatic cancer cells. [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 3801.
Abstract 3813: Role of CDKN2B antisense RNA 1 in Epstein-Barr virus associated gastric carcinoma
Authors: Torres Keila , Olivares Wilda , Carrasco Gonzalo , Rodriguez Andres , Corvalan Alejandro H. 
Published: June 2023

Abstract
Background: Epstein-Barr Virus (EBV)-associated gastric carcinoma (GC) (EBVaGC) is a subtype of GC which represents approximately 10% of this tumor. CDKN2B antisense RNA 1 (CDKN2B-AS1) is a long non-coding RNA associated with chronic diseases like cardiovascular disease and cancer. This study aimed to evaluate if the loss of CDKN2B-AS1 shifted the balance of the competing endogenous RNA (ceRNA) networks favoring an apoptosis resistant phenotype through ebv-miR-BART4-5p/BID in EBVaGC.
Material and Methods: Seven gastric cancer cell lines were used to determine the expression of CDKN2B-AS1. Specific cell lines were used for CDKN2B-AS1 inhibition assays, the transfection of ebv-miR-BART4-5p and the binding between CDKN2B-AS1 and ebv-miR-BART4-5p. The detection of BID protein was determined by Western Blot. To validate the in vitro results, we detected CDKN2B-AS1, BID, and ebv-miR-BART4-5p expression levels by RT-qPCR in four EBVaGC positive and five negative cases. Apoptosis was detected by in situ hybridization (ISH).
Results and Discussion: CDKN2B-AS1 is expressed at higher levels in NCI-N87 and SNU-1 cell lines and at lower levels in AGS and KATO-III. A significant decrease in BID protein expression was observed after co-transfection with ebv-miR-BART4-5p and CDKN2B-AS1 inhibitor. However, these results were not significant at mRNA level. The luciferase assay validated the predicted binding between ebv-miR-BART4-5p and CDKN2B-AS1. In EBVaGC samples, a significant decrease in BID expression and cleaved caspase-3 in the presence of miR-BART4-5p was observed. Our results show that decreasing CDKN2B-AS1 expression favors viral miR binding on BID mRNAs through ceRNA networks. Also, these results could explain why positive EBVaGCs have lower apoptosis rate than EBVaGC negative cases.
Grant support: ANID/FONDECYT/POSTDOCTORADO/3201028, CONICYT-FONDAP-15130011, FONDECYT-1191928
Citation Format: Keila Torres, Wilda Olivares, Gonzalo Carrasco, Andres Rodriguez, Alejandro H. Corvalan. Role of CDKN2B antisense RNA 1 in Epstein-Barr virus associated gastric 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 3813.
Abstract 3854: TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC
Authors: Tanimoto Azusa , Cardnell Robert J. , Morris Benjamin B. , Ramkumar Kavya , Li Shen , Wang Qi , Stewart Allison C. , Gay Carl Michael , Wang Jing , Averett Byers Lauren 
Published: June 2023

Abstract
Background: Small cell lung cancer (SCLC) is a highly lethal malignancy, with rapidly acquired chemotherapy resistance. Some studies have reported that Wnt signaling pathway activation promoted cell proliferation and was correlated with chemo-resistance in SCLC. None of the therapies targeting Wnt pathway components of the transmembrane and the cytoplasm have been successful in a clinical application due to toxicity and insufficient efficacy. However, targeting Wnt signaling inside the nucleus has been drawing increasing attention as cancer therapeutics. TRAF2 and NCK-interacting protein kinase (TNIK), which interacts with downstream effectors, TCF4/β-catenin transcriptional complex, is an essential activator of Wnt target genes. TNIK is highly expressed in several cancers for cell proliferation, thus TNIK is expected as a novel druggable target. On the other hand, the question remains whether TNIK is a critical target in SCLC. We hypothesize that a TNIK inhibitor has potent anti-tumor effects in SCLC and its promising biomarkers exist.
Methods: We used 29 SCLC cell lines including all four subtypes defined by differential expression of transcription factors ASCL1, NEUROD1, POU2F3, and inflamed gene signature (SCLC-A, N, P, and I, respectively) to evaluate the effect of a TNIK inhibitor, NCB-0846 in vitro. We correlated NCB-0846 IC50 values with proteomic profiling (Reverse Phase Protein Array, RPPA) data. Protein expression was examined by western blotting.
Results: NCB-0846 markedly reduced cell proliferation in SCLC-N and P cell lines. There was a strong positive correlation between cMyc and the efficacy of NCB-0846 (r=-0.484, P&lt;0.01), while a negative correlation between TTF1 and the efficacy (r=0.569, P&lt;0.01). Additionally, NCB0846 decreased the expression of cMyc in cMyc-high/TTF-1 low SCLC cells.
Conclusions: These findings indicate that TNIK inhibitors may be a new personalized molecular-targeted therapy in cMyc-high/TTF-1-low SCLC.
Citation Format: Azusa Tanimoto, Robert J. Cardnell, Benjamin B. Morris, Kavya Ramkumar, Shen Li, Qi Wang, Allison C. Stewart, Carl Michael Gay, Jing Wang, Lauren Averett Byers. TNIK inhibition as a novel therapeutic in cMyc high/TTF1 low SCLC. [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 3854.
Abstract 4885: APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines
Authors: Yu Camilla , Petty Aaron , Vargas Roberto 
Published: June 2023

Abstract
Background: The majority (80%) of endometrial cancer (EC) related mortality is due to high-grade tumor histology, which harbor high rates of TP53 mutations. APR-246 is a small-molecule drug designed to restore WT p53 signaling in TP53-mutant cancers and has yet to be explored in EC. We aimed to test the cytotoxic potential for APR-246 in EC and its downstream impact.
Methods: Using 3 parental EC cell lines with differing TP53 statuses, JHUEM2 (WT), Hec108 (hetero P151H), and Hec1B (R248Q), we generated dose-response curves for APR-246. Cells were treated for 24 hours and viability assessed with CellTiter-Glo after 9 days. To assess for mutation specific effect, we generated dose-response curves using a WT non-targeting control (NTC), CRISPR/Cas9 KO of TP53, and five KO cell lines complemented with 5 common TP53 mutations (R248Q, R248W, R273C, R273H, Y220C). Western blot analysis was performed to assess for p53, p21, PUMA, GADD45, and NOXA using whole-cell lysates, after treatment with 20μM of APR-246 for 24 hours. To further evaluate for a time-dependent effect, 2 representative variants (R248Q and R273C) after 6 and 24 hours of incubation with 50μM APR-246 and 10μM of Nutlin-3.
Results: APR-246 demonstrated a negative, dose-dependent effect on cell viability in all EC cell lines. IC50s for JHUEM2, Hec108, and Hec1B were 2.5μM, 4.3μM, and 4.5μM respectively. For NTC, the IC50 was (1.7μM), while TP53-KO (7.5μM) demonstrated similar IC50 values to the variants (6.5-11.9μM). Two variants (Y220C and R248W), had significantly (&lt;0.001 and &lt;0.01 respectively) higher IC50 values (11.9 and 9.1 μM respectively). In Western blot analysis, no p53 downstream signaling via p21, GADD45, PUMA, and NOXA was observed for any variants.
Conclusions: Our results demonstrate that APR-246's cytotoxic effects in EC seem to be p53-independent. Potential mechanisms for the anti-neoplastic effects of APR-246 include activity targeting antioxidant pathways demonstrated in other solid tumors and provides an area for further investigation in TP53mut EC.
Citation Format: Camilla Yu, Aaron Petty, Roberto Vargas. APR-246 cytotoxic effects are TP53 independent in endometrial cancer cell lines. [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 4885.