tbuckley/cabot-search huggingface dataset:
Abstract 1079: Distinct DNA methylation targets by aging and chronic inflammation
Authors: Satoshi Yamashita, Sohachi Nanjo, Emil Rehnberg, Naoko Iida, Hideyuki Takeshima, Takayuki Ando, Takao Maekita, Toshiro Sugiyama, Toshikazu Ushijima
Journal: Cancer Research (2020)

Abstract Aberrant DNA methylation is involved in many types of human cancers, and is induced by aging. In addition, it is known to be induced by chronic inflammation, and this inflammation-induced DNA methylation is considered as acceleration of age-related methylation. However, few studies addressed target genomic regions of age-related and inflammation-induced DNA methylation in a genome-wide manner. We previously demonstrated that Helicobacter pylori(HP) infection induces aberrant DNA methylation potently in human and gerbil gastric mucosa [Niwa, Cancer Res, 70:1430, 2010; Ushijima, Clin Cancer Res, 18:923, 2012]. Here, taking advantage of the potent methylation induction, we aimed to clarify the targets of methylation induction by aging and inflammation. We collected gastric mucosae from i) HP-never infected young individuals (under 40 years; n=4; G1), ii) HP-currently infected young individuals (n=4; G2), iii) HP-never-infected old individuals (above 60 years; n=4; G3), and vi) HP-currently-infected old individuals (n=4; G4). DNA methylation of 482,421 CpG probes was analyzed by Infinium Human Methylation 450K, and the probes were grouped into 270,249 genomic blocks. It was revealed that high levels of methylation were induced in 44,461 (16.5%) genomic blocks by current inflammation (G2/G1), even after correction of the influence of leucocyte infiltration. 61.8 % of the hypermethylation was acceleration of age-related methylation (G3/G1) while 21.6 % was specific to inflammation. Regions with H3K27me3 were frequently hypermethylated both by aging and inflammation. Basal methylation levels were essential for age-related hypermethylation while even regions with little basal methylation were hypermethylated by inflammation. When limited to promoter CpG islands, being a microRNA gene and high basal methylation levels strongly enhanced hypermethylation while H3K27me3 strongly enhanced inflammation-induced hypermethylation. Inflammation was capable of overriding active transcription. In young gastric mucosae (G2/G1), genes with high expression and frequent mutations in gastric cancers were more frequently methylated than in old ones (G4/G3).Methylation by inflammation was not simple acceleration of age-related methylation. Targets of aberrant DNA methylation were different between young and old gastric mucosae, and driver genes were preferentially methylated in young gastric mucosa [Yamashita, Clin Epigenet, in press]. Citation Format: Satoshi Yamashita, Sohachi Nanjo, Emil Rehnberg, Naoko Iida, Hideyuki Takeshima, Takayuki Ando, Takao Maekita, Toshiro Sugiyama, Toshikazu Ushijima. Distinct DNA methylation targets by aging and chronic inflammation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1079.
Abstract 2230: MG1131, a novel TIGIT-targeting monoclonal antibody, enhances anti-tumor immune responses by modulating NK and T cell activity
Authors: Jeewon Lee, Munkyung Kim, Hye-mi Nam, Joong Hyuk Sheen, Eun Jung Song, Hye In Yum, So Jung Lim, Hye-Young Park
Journal: Cancer Research (2020)

Abstract As the recent rise of immune checkpoint inhibitors has resulted in durable clinical outcomes in cancer patients, the need for a newer and more widely effective target for immunotherapy has been vigorously sought in the field; T cell immunoreceptor with Ig and ITIM domain (TIGIT) is an immune checkpoint molecule expressed on CD8+ T cells, CD4+ T cells, NK cells, and regulatory T cells (Treg). TIGIT induces exhaustion of effector T cells (Teff) and NK cells in the tumor microenvironment via engagement with its ligand PVR (CD155) which is dominantly expressed on malignant tumor cells. After initial screening processes from a synthetic library, MG1131 clone was chosen based on the strongest binding affinity to human TIGIT and the superior PVR-blocking activity. MG1131 was cross-reactive with the cynomolgus monkey TIGIT, but not with the mouse TIGIT. Our in vitro efficacy data demonstrated that MG1131 activated NF-κB signaling in T cells, and enhanced NK-mediated tumor killing activities in a PVR-dependent manner. In vitro Treg suppression assays showed that MG1131 inhibited immunosuppressive functionality of Treg, leading to restoration of proliferation and IFN-γ secretion capacities of Teff even in the presence of Treg. In addition, expression levels of TIGIT on CD8+ T cells from PBMCs of cancer patient samples were higher compared with other immune inhibitory molecules such as PD-1, Tim-3, CTLA-4, or LAG-3, and the blockade of TIGIT by MG1131 resulted in increased IFN-γ secretion. Thus, our data indicate that MG1131 is a promising candidate for cancer immunotherapy by modulating NK and T cell functions. Citation Format: Jeewon Lee, Munkyung Kim, Hye-mi Nam, Joong Hyuk Sheen, Eun Jung Song, Hye In Yum, So Jung Lim, Hye-Young Park. MG1131, a novel TIGIT-targeting monoclonal antibody, enhances anti-tumor immune responses by modulating NK and T cell activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2230.
Abstract 4169: The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia
Authors: Fuling Zhou, Dongdong Zhang
Journal: Cancer Research (2020)

Abstract Chemoresistance and high incidence of relapse in acute myeloid leukemia (AML) patients are associated with thioredoxin (Trx) overexpression. Thus, targeting the Trx system has emerged as a promising approach to treating AML. Both arsenicals and azelaic acid (AZA) are thioredoxin reductase inhibitors (TrxR) and possess antileukemic effects. In this study, to exploit agents with higher potency and lower toxicity, we got some organic arsenicals and further synthesized a series of targeted compounds by binding AZA to organic arsenicals, and then screened the most effective one, N-(4-(1, 3, 2-dithiarsinan-2-yl) phenyl)-azelamide (A-Z2). A-Z2 showed a stronger inhibitory effect against TrxR activity and in AML cell lines than did AZA or arsenicals. Additionally, A-Z2 was less toxic to healthy cells compared with traditional chemotherapeutic drugs. A-Z2 induces apoptosis by collapsing of mitochondrial membrane potential, reducing ATP level, releasing of cytochrome c and TNF-α, activating of caspase 9, 8 and 3. Analysis of the mechanism revealed that A-Z2 activates the intrinsic apoptotic pathway by directly selectively targeting TrxR/Trx and indirectly inhibiting NF-κB. A-Z2's better efficacy and safety profile against arsenicals and azelaic acid were also evident in vivo. A-Z2 had better plasma stability and biological activity in rats. A-Z2-treated mice displayed significant symptom relief and prolonged survival in a patient-derived xenograft (PDX) AML model. Herein, our study provides a novel antitumor candidate and approach for treating AML. Keywords: Acute myeloid leukemia, Thioredoxin reductase, TrxR inhibitor, organic arsenicals, NF-κB Citation Format: Fuling Zhou, Dongdong Zhang. The novel thioredoxin reductase inhibitor A-Z2 triggers intrinsic apoptosis and shows efficacy in the treatment of acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4169.
Abstract LB-221: Aggresome-based classification is a promising prognostic marker for pediatric choroid plexus tumors
Authors: Nada Amer, Hala Taha, Dina Hesham, Noura Mahmoud, Moatasem Elayadi, Amal Mossab, Ayda Youssef, Mohamed Elbeltagy, Mohamed Saad Zaghloul, Ahmad Abdel Azziz, Shahenda El-Naggar
Journal: Cancer Research (2020)

Abstract Protein misfolding and aggregation result in proteotoxic stress, and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. Aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Our previous work revealed the presence of aggresomes in pediatric choroid plexus tumors (CPT). CPTs are rare neoplasms comprised of three pathological subgroups; choroid plexus carcinoma (CPC), a grade III tumor, atypical choroid plexus papilloma (ACPP), a grade II tumor, and choroid plexus papilloma (CPP), a grade I tumor. In the current study, we aimed to investigate the prognostic value of aggresomes-positivity and if it could be used to improve the disease subclassification. Forty two pediatric CPT tumor samples were stratified into two molecular subgroups; Cluster “A", and “B”, using Illumina Infinium Methylation EPIC BeadChip array. Kaplan Meier analysis showed that “cluster B” is associated with significantly shorter overall survival (OS) and event free survival (EFS) with P= 0.008 and P =0.007 respectively. Aggresomes were detected in 64.2% of samples using immunohistochemistry and they were distributed among different pathological and molecular subgroups. The presence of aggresomes significantly correlated with patient outcome in both OS (P = 0.057) and EFS (P = 0.051). The survival-based cutoff determination was performed using various percentages of aggresomes; ranging from 10% to 50%. Aggresome presence maintained significance at all cutoffs, yet the 25% cutoff had the highest impact in OS and EFS (P = 0.001). Moreover, the classification based on the 25% cutoff concurred with the methylation signature of low-risk “A” and high-risk “B” clusters. Hence, the detection of aggresomes in CPTs provides a new prognostic marker supporting histopathological tumor classification. Citation Format: Nada Amer, Hala Taha, Dina Hesham, Noura Mahmoud, Moatasem Elayadi, Amal Mossab, Ayda Youssef, Mohamed Elbeltagy, Mohamed Saad Zaghloul, Ahmad Abdel Azziz, Shahenda El-Naggar. Aggresome-based classification is a promising prognostic marker for pediatric choroid plexus tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-221.
Abstract 1937: BPR6K609: An Aurora kinase inhibitor targeting small cell lung cancer with MYC amplification
Authors: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Wan-Ping Wang, Chia-Hua Tsai, Yen-Ting Chen, Yu-Jie Su, Ming-Chun Hung, Zhong-Wei Wu, Mine-Hsine Wu, Teng-Kuang Yeh, Ching-Ping Chen, Jen-Shin Song, Chiung-Tong Chen, Chuan Shih
Journal: Cancer Research (2020)

Abstract Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, leading to ~30,000 deaths each year in the United States. SCLC patients often present with metastasis at time of diagnosis, excluding surgery as a treatment option. While patients show high response rate to standard chemotherapy such as cisplatin/etoposide, they soon develop drug resistance and disease progression. Therefore, new therapeutic strategies are urgently needed for SCLC. BPR6K609S0 is a novel Aurora kinase inhibitor which has been designed to inhibit the kinase activity of Aurora A, and induces proteasome-mediated degradation of MYC. The BPR6K609S0 active molecule provokes cell apoptosis and inhibits proliferation of several SCLC cell lines with IC50 &amp;lt; 100 nM. Oral administration of BPR6K609 induces &amp;gt;60 % tumor regression in a NCI-H446 xenograft mouse model. In addition, BPR6K609 further reduces tumor progression in NCI-H446 xenograft mice pre-treated with LY3295668, an Aurora A-selective inhibitor which is currently under clinical investigation. These results support the clinical potential of BRP6K609S0 for the treatment of SCLC. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Yi-Yu Ke, Wen-Hsing Lin, Wan-Ping Wang, Chia-Hua Tsai, Yen-Ting Chen, Yu-Jie Su, Ming-Chun Hung, Zhong-Wei Wu, Mine-Hsine Wu, Teng-Kuang Yeh, Ching-Ping Chen, Jen-Shin Song, Chiung-Tong Chen, Chuan Shih. BPR6K609: An Aurora kinase inhibitor targeting small cell lung cancer with MYC amplification [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1937.
Patients’ Preoperative Expectations of Total Knee Arthroplasty and Satisfaction With Outcomes at One Year: A Prospective Cohort Study
Authors: Gillian A. Hawker, Barbara L. Conner‐Spady, Eric Bohm, Michael J. Dunbar, C. Allyson Jones, Bheeshma Ravi, Tom Noseworthy, Donald Dick, James Powell, Paulose Paul, Deborah A. Marshall
Journal: Arthritis & Rheumatology (2020)

Objective To assess the relationship between patients’ expectations for total knee arthroplasty (TKA) and satisfaction with surgical outcome. Methods This prospective cohort study recruited patients with knee osteoarthritis (OA) ages ≥30 years who were referred for TKA at 2 hip/knee surgery centers in Alberta, Canada. Those who received primary, unilateral TKA completed questionnaires pre‐TKA to assess TKA expectations (17‐item Hospital for Special Surgery [HSS] TKA Expectations questionnaire) and contextual factors (age, sex, Western Ontario and McMaster Universities Osteoarthritis Index pain score, Knee Injury and Osteoarthritis Outcome Score physical function short form [KOOS‐PS], 8‐item Patient Health Questionnaire depression scale, body mass index [BMI], comorbidities, and prior joint replacement), and 1‐year post‐TKA to assess overall satisfaction with TKA results. Using multivariate logistic regression, we examined the relationship between TKA expectations (HSS TKA outcomes considered to be very important) and postoperative satisfaction (very satisfied versus somewhat satisfied versus dissatisfied). Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results At 1 year, 1,266 patients with TKA (92.1%) reported their TKA satisfaction (mean ± SD age 67.2 ± 8.8 years, 60.9% women, and mean BMI 32.6 kg/m 2 ); 74.7% of patients were very satisfied, 17.1% were somewhat satisfied, and 8.2% were dissatisfied. Controlling for other factors, an expectation of TKA to improve patients’ ability to kneel was associated with lower odds of satisfaction (adjusted OR 0.725 [95% CI 0.54–0.98]). An expectation of TKA to improve psychological well‐being was associated with lower odds of satisfaction for individuals in the lowest tertile of pre‐TKA KOOS‐PS scores (adjusted OR 0.49 [95% CI 0.28–0.84]), but higher odds for those in the highest tertile (adjusted OR 2.37 [95% CI 1.33–4.21]). Conclusion In patients with TKA, preoperative expectations regarding kneeling and psychological well‐being were significantly associated with the level of TKA satisfaction at 1 year. Ensuring that patients’ expectations are achievable may enhance appropriate provision of TKA.
Abstract 1348: Optimizing experimental design for high-parameter protein analysis using BD AbSeq technology
Authors: Punya Narayan, Hye-Won Song, Margaret Nakamoto, Elisabeth Walczak, Katherine Lazaruk, Stefanie Mortimer
Journal: Cancer Research (2020)

Abstract High-throughput single cell RNA sequencing (RNA-seq) has recently emerged as a powerful tool for profiling complex cell populations. While traditional single cell RNA-seq captures information about transcript expression, recent technological advances using oligo-conjugated antibodies enable simultaneous detection of proteins alongside mRNA in high-throughput sequencing. This multiomic technology enables high parameter protein analysis that can simultaneously discriminate 100 protein markers. However, experiment workflow time and cost can escalate quickly with high plexy assays. To address these issues we investigated a number of methods to decrease cost and assay time while maintaining data quality using the BD® AbSeq on the BD Rhapsody™ Single-Cell Analysis sequencing system. To begin, we investigated the performance of 20 core proteins when used in a 20plex, 40plex, 60plex, 80plex, or 100plex in model cells. Results from 3 experiments showed that performance was maintained as plexy increased, however rigorous experimental approaches must be followed to minimize impact on specificity or sensitivity. After establishing performance of this 20plex we investigated pre-cocktailing of antibodies as a method to shorten the day-of-experiment workflow, and mixing of oligo-labeled and unlabeled antibodies to high-expressing proteins (“signal muting”) as a way to decrease sequencing costs. Results showed a decrease in specificity as soon as 24 hours after the cocktailing of antibodies and increasing non-specific binding with longer cocktail storage times. On the other hand, signal muting was effective at decreasing sequencing requirements by up to 70%, without impacting data for high expressors. Together these results can be used to aid in optimizing experimental design when working with high-plex AbSeq protein panels, to better harness the information gained from multiomic single cell sequencing data. For Research Use Only. Not for use in diagnostic or therapeutic procedures.BD, the BD Logo, and Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2019 BD. All rights reserved. Citation Format: Punya Narayan, Hye-Won Song, Margaret Nakamoto, Elisabeth Walczak, Katherine Lazaruk, Stefanie Mortimer. Optimizing experimental design for high-parameter protein analysis using BD AbSeq technology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1348.
Abstract 701: Immunogenicity risk assessment and mitigation tools
Authors: Amin Osmani, Sofie Pattijn, Jana Schockaert, Aurélie Mazy, Chloé Ackaert
Journal: Cancer Research (2020)

Abstract New immuno-oncology mAbs or agents with other structures have revolutionized treatment options for several malignancies in the past few years, and more are currently being evaluated in the clinic. The development of new therapeutics comes with a series of challenges and questions, of which one is the risk for unwanted immunogenicity which can lead to decreased efficacy and safety concerns. Today, both in silico and in vitro preclinical tools are available to identify early on therapeutic candidates with a high immunogenicity risk potential. Additionally, certain tools can be used to mitigate the immunogenicity potential, and thus improve and accelerate therapeutic drug development and reduce the number of clinical failures. Often used as a first step is an in silico T cell epitope prediction algorithm such as NetMHCIIpan which can be used to assess and compare the immunogenic potential of the lead candidates and guide de-immunization strategies. Further monitoring of the immunogenic risk can be performed using different in vitro assays: a peptide screen assay, to enable the exclusion of immunogenic peptides and the inclusion of low risk sequences; a dendritic cell activation assay to assess immunogenicity signals for the whole product; the MAPPs or MHC Associated Peptide Proteomics, assay to follow uptake, processing and presenting of biotherapeutics by dendritic cells and identify specific regions of concern, and; in vitro T cell proliferation and activation assays to determine and rank the immunogenic risk of the test proteins. The compilation of the different datasets and translation of the results into a comprehensive risk management plan, allows selection of the best candidates to move forward into humans, deimmunization of test candidates and identification and discontinuation of the high-risk candidates as early as possible. Citation Format: Amin Osmani, Sofie Pattijn, Jana Schockaert, Aurélie Mazy, Chloé Ackaert. Immunogenicity risk assessment and mitigation tools [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 701.
Abstract 6274: Radiosensitizing effect of beta-Apopicropodophyllin is mediated from ER stress against colorectal cancer
Authors: A-Ram Kang, Na-Kyung Lee, Hyun-Jin Shin, Hong-Duck Um, Jong Kuk Park
Journal: Cancer Research (2020)

Abstract β-Apopicropodophyllin (APP) is a synthesized derivative of podophyllotoxin (PPT), which is a natural product that has been used as a traditional drug to decrease immunosuppression, exert antiviral effects for the treatment of influenza, venereal warts, measles and herpes, and even to treat skin cancer. In this study, we tested whether β-apopicropodophyllin (APP) could act as a radiosensitizer in colorectal cancer. To demonstrate radiosensitizing activity of APP, several in vitro tests such as clonogenic assay, immunoblotting, Annexin V-Propidium iodide (PI) assay, detection of mitochondrial ROS/intracellular of H2O2, mitochondrial membrane potential detection were performed. We also tested in vivo radiosensitizing activity of APP as performing colorectal cancer-derived xenograft experiments with mice, and detected tumor volumes and apoptotic cell death. Clonogenic assay showed a combination of APP and γ-ionizing radiation (IR) inhibits cell growth and increases cell death in colorectal cancer cells. Several signal transduction pathways were examined for its potential involvement, and then these results indicated enhanced ER stress is main radiosensitization effect of APP as assessed by immunoblotting analyses. In addition, disrupted mitochondrial membrane potential and increased reactive oxygen species (ROS) were also observed in cells co-treated with APP and IR; these phenomena were followed by the cytosolic release of cytochrome c and consequent activation of caspase-3 and -9. Interestingly, pharmaceutical inhibition of JNK or p38, which prevents caspase activation, blocked the APP/IR-induced activations of ER stress and apoptotic cell death. Therefore, our results implied APP has a radiosensitizing function to induce apoptotic cell death via activation of ER stress, disruption of mitochondrial membrane potential, and induction of the caspase pathway via JNK or p38 induction. Citation Format: A-Ram Kang, Na-Kyung Lee, Hyun-Jin Shin, Hong-Duck Um, Jong Kuk Park. Radiosensitizing effect of beta-Apopicropodophyllin is mediated from ER stress against colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6274.