tbuckley/cabot-search huggingface dataset:
Abstract 5256: Toward biomarkers discovery: Profiling triple-negative breast cancer cells by cell-SELEX
Authors: Simona Camorani, Francesco Leonetti, Francesca Collina, Monica Cantile, Gerardo Botti, Antonella Zannetti, Monica Fedele, Laura Cerchia
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) is a high heterogeneous group of tumors with a distinctly aggressive nature and high rates of relapse. So far, the lack of any known targetable proteins has not allowed a specific anti-tumor treatment, thus the identification of novel agents for specific TNBC recognition and treatment is desperately needed. Nucleic acids aptamers are emerging as the most promising candidates for targeting tumor cells. They are also termed "chemical antibodies" because their form unique tertiary structures, which allow specific binding to their target molecules. Recently, by cell-SELEX integrated to advanced Next Generation Sequencing and bioinformatics, we isolated a panel of six nuclease-resistant RNA aptamers able to bind at high affinity to TNBC cells, discriminating them from both normal cells and non-TNBC breast cancer cells, and interfere with their growth as mammospheres. Also, they diversify TNBC histological specimens in a tissue microarray without recognizing samples from both ER+, PR+, HER2+ breast cancers and normal adjacent tissues. Here, short versions of the aptamers have been generated, by truncating their length from 84 nt up to nearly 30 nt, which preserve efficacious targeting and anti-tumor properties as the parental moieties. In order to identify the targets of the above aptamers, which might be important surface cancer biomarkers crucial for the malignant phenotype, different biochemical approaches are harnessed that include aptamer-mediated affinity purification coupled to Mass Spectrometry and/or antibody array for human soluble receptors. Binding analyses on recombinant proteins, cells or tissues are used to verify the putative targets. Results obtained so far indicate that the target of one of the six aptamers is a secreted protein tightly and specifically associated to TNBC cell surface and with a poor prognosis. This protein identification and the functional role of its targeting by the aptamer will be shown here in detail. The proposed cell-targeting aptamer strategy could provide an important new avenue for selective TNBC therapy. Citation Format: Simona Camorani, Francesco Leonetti, Francesca Collina, Monica Cantile, Gerardo Botti, Antonella Zannetti, Monica Fedele, Laura Cerchia. Toward biomarkers discovery: Profiling triple-negative breast cancer cells by cell-SELEX [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 5256.
Abstract 994: Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects
Authors: Carlo Marchetti, Isak Tengesdal, Charles Dinarello, Mayumi Fujita
Journal: Cancer Research (2020)

Abstract Introduction: Melanoma NLRP3 inflammasome activation is involved in tumor progression and melanoma-induced immunosuppression via IL-1β-mediated effect. Abstract: Melanoma-associated inflammation participates in the generation of a tumor permissive environment, which promotes tumor progression and metastasis. The pro-inflammatory cytokine IL-1β mediates several inflammatory diseases and the modulation of the immune system. In the context of malignancy, IL-1β is a validated target in mouse models of cancer, including melanoma, where the cytokine contributes to immunosuppression, angiogenesis, metastasis, and regulation of myeloid derived suppressor cells. In this study, we demonstrate that the NLRP3 inflammasome drives the maturation of the pro-inflammatory cytokine IL-1β in melanoma cells. Accordingly, analysis of melanoma biopsies (N=461) showed increased NLRP3 expression in the lesions which correlates with the IL-1β levels. In melanoma-bearing mice, NLRP3 inhibition with a clinically evaluated NLRP3 inflammasome inhibitor OLT1177 (dapansutrile), showed to decrease melanoma progression and tumor-induced inflammation reducing the circulating levels of IL-6, G-CSF, and VEGF compared to vehicle tumor-bearing mice. Analysis of myeloid-derived suppressor cell (MDSC) populations revealed that NLRP3 inflammasome inhibition was sufficient to prevent MDSCs expansion (both PMN-MDSCs and M-MDSCs), restoring the population to the non-tumor-bearing level. The effect observed on MDSCs in tumor-bearing mice following NLRP3 inhibition resulted in increased NK cells activation in primary tumors (Figure). These data establish a new correlation between IL-1β, NLRP3, melanoma-induced immunosuppression and tumor progression. Considering that NLRP3 inhibition resulted in decreased tumor-induced immune evasion as well as an increased tumoricidal immune response, we evaluated the effect of the addition of NLRP3 inhibition to checkpoint inhibition. Tumor bearing mice treated with OLT1177 and anti-PD-1 showed reduced tumor progression compared to the single-agent treatments. In conclusion, NLRP3 inflammasome inhibition was successful in preventing IL-1β processing in melanoma cells and tumor progression. These findings suggest that NLRP3 may represent a potential therapeutic target for melanoma. Citation Format: Carlo Marchetti, Isak Tengesdal, Charles Dinarello, Mayumi Fujita. Tumor NLRP3 drives melanoma progression and immunosuppression by IL-1b-mediated host pro-tumor effects [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 994.
Clinical Utility of 18F-FDG PET/CT in Staging Localized Breast Cancer Before Initiating Preoperative Systemic Therapy
Authors: Heidi Ko, Yaser Baghdadi, Charito Love, Joseph A. Sparano
Journal: Journal of the National Comprehensive Cancer Network (2020)

18F-fluorodeoxyglucose PET/CT is recommended as an optional study in the current NCCN Clinical Practice Guidelines in Oncology for Breast Cancer after CT of the chest, abdomen, and pelvis with contrast and bone scan (CTBS) in stage IIA-IIIC breast cancer. We evaluated our experience with the use of PET/CT in this setting before beginning primary systemic therapy (PST) prior to planned surgery.
Abstract 11477: Improving Arrhythmic Risk Stratification in Non-Ischemic Dilated Cardiomyopathy Through the Evaluation of Novel Scar Characteristics Using CMR
Authors: Brian P Halliday, Gabriel Balaban, Caroline Mendonca Costa, Wenjia Bai, Bradley Porter, Suzan Hatipoglu, Nuno Dias Fereira, Cemil Izgi, Ben Corden, Upasana Tayal, James S Ware, Gernot Plank, C. Aldo Rinaldi, Daniel Rueckert, Sanjay K Prasad, Martin Bishop
Journal: Circulation (2019)

Introduction: Improving patient selection for implantable cardioverter defibrillators (ICDs) in non-ischemic dilated cardiomyopathy (DCM) is an important unmet need. Hypothesis: Novel scar metrics ...
Abstract 3148: FOXC1 expression is associated with a triple-negative basal-like phenotype in breast cancer
Authors: William C. Cho, Victor W. Ma, Wah Cheuk, Grace Y. So, Rebecca Y. Chin
Journal: Cancer Research (2020)

Abstract Introduction: Triple-negative breast carcinoma (TNBC) is a group of aggressive tumors that are resistant to hormonal therapy. Forkhead box C1 (FOXC1) has been shown to play a crucial role in cancer pathogenesis by cancer stem cell regulation, epithelial to mesenchymal transition and tumor progression in basal-like breast cancer (BLBC). This study examined the expression of FOXC1 in basal-like TNBC, which may potential be exploited as a treatment target for this group of tumors. Materials and Methods: Immunohistochemical Peroxidase-DAB system and Opal immunofluorescence staining system were employed to detect FOXC1 and cytokeratin 14 (CK14) expressions in 44 formalin-fixed paraffin-embedded (FFPE) invasive ductal breast carcinoma (IDC) and 150 IDC samples on tissue microarray. CK14 was used to identify the BLBC subtype. The staining was scored semi-quantitatively according to the intensity with a mean score from 0-4. Results: CK14 identified 15 (34%) BLBC in the FFPE tissues and 24 (16%) BLBC in the samples on tissue microarray. Of the 44 FFPE tissues, FOXC1 expression was observed in 100% of the BLBC and 83% of TNBC, while it was only found in 15% of non-TNBC. The mean staining intensity of FOXC1 was lower in non-TNBC (0.30) compared to TNBC (2.16) and basal-like TNBC (2.60). These findings were confirmed in the tissue microarray, which also revealed a strong positive correlation of FOXC1 with basal-like TNBC. In addition, our results showed that FOXC1 was more frequently expressed in ER-negative (22%), PR-negative (21%) and HER2-negative (19%) breast cancers than in ER-positive (3%), PR-positive (3%) and HER2-positive (5%) breast cancers. Moreover, FOXC1 expression was significantly associated with high tumor grade (p = 0.000041) and high tumor-infiltrating lymphocytes (TILs) (p = 0.000001). Conclusion: FOXC1 is highly expressed in TNBC, particularly among the basal-like subgroup, as opposed to other breast cancers. It accurately classifies the BLBC subtype which may be used as a surrogate marker for this molecular subtype. We find that FOXC1 has an inverse correlation with ER, PR and HER2, as well as a positive correlation with tumor grade and TILs. Our finding suggests that FOXC1 may serve as a potential treatment target for basal-like TNBC. Citation Format: William C. Cho, Victor W. Ma, Wah Cheuk, Grace Y. So, Rebecca Y. Chin. FOXC1 expression is associated with a triple-negative basal-like phenotype in breast 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 3148.
Abstract 2041: Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model
Authors: Keyur Naik, Malvin N. Janal, Jason Chen, Daniel E. Bandary, Branden Brar, Aditi Bhattacharya
Journal: Cancer Research (2020)

Abstract Oral cancer is a painful and debilitating type of cancer. Oral cancer patients frequently experience severe pain while eating and talking. Pain is attributed to neuronal sensitization by the release of chemical mediators from the cancer cells and cancer microenvironment. Not all oral cancers are painful. Patients with painful oral cancers are more likely to have worse prognosis and metastatic disease, and their pain is not well managed with NSAIDs or opioid analgesics. Therefore, there is an unmet clinical need to identify the underlying mechanisms of oral cancer pain. This study was designed to identify pathological lesions associated with increased pain in a preclinical model of oral cancer and pain. Forty C57BL/6 female mice were treated with 4-nitroquinoline 1-oxide (4NQO) for 16 weeks, and followed for the development of tongue lesions for 12 weeks. Concurrently, change in nociceptive behavior (i.e., the animal equivalent of pain behavior) was measured using a validated operant assay and device for measuring functional mechanical allodynia (the dolognawmeter). Nociception (pain) scores and histopathological data were obtained from 36 animals. Mice developed a spectrum of tongue and esophageal lesions including hyperkeratoses, papillomas (exophytic lesions), dysplasias and cancers. Papillomas included lesions with benign and dysplastic pathological features, indicating that both lesion types were in the continuum of malignant transformation. Mice harbored lesions associated with low pain scores (n=9), intermediate pain scores (n=16) and high pain scores (n=11). Three pathological subsets of squamous cell carcinomas (SCCs) were identified that displayed stromal invasion (iSCC), deep stromal invasion &amp;gt;1.5mm depth (diSCC) and cancers with exophytic and invasive morphology associated with papillary lesions (pSCCs). Increased nociceptive behavior was associated with pSCCs in univariate and multivariate analyses. Cancers of the pSCC subtype are expected to be enriched for expression and release of nociceptive mediators. The study demonstrates that the 4NQO model recapitulates human cancer with respect to development of cancers differing in level of cancer associated nociception. Citation Format: Keyur Naik, Malvin N. Janal, Jason Chen, Daniel E. Bandary, Branden Brar, Aditi Bhattacharya. Lesion pathology and oral-cancer associated pain in the 4NQO oral carcinogenesis model [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 2041.
Abstract 5161: Validation of drug candidates targeting dormant cancers in live cells as a key for successful translation into the clinic
Authors: Alexei Belenky, Alexandra Kuznetsova, Michael Frid, Felix Chapovsky, Marc Duey, Maria Vilenchik
Journal: Cancer Research (2020)

Abstract Thermal shift assay was utilized to demonstrate target engagement of drug candidate compounds to their specific targets. We explored novel cancer dormancy targets: DYRK1B and AXL kinases and assessed interaction with corresponding small molecule inhibitors. We demonstrated the correlation of direct target binding with ASMS (affinity selected mass spectrometry) and mechanism of action with cell-based phenotypic assays (using flow cytometry) for previously identified and current clinical candidates. We demonstrated that the above described approach can characterize and potentially predict clinical activity of novel molecules. Herein we investigated DYRK1B inhibitors from an azaindole-quinoline series. It was shown earlier that these molecules have picomolar activity in in vitro assays against DYRK1 kinases (DYRK1B and DYRK1A) and now we confirmed their DYRK1B specificity in cells as well as their activity against dormant cancers. We suggest that described inhibitors are valid clinical candidates for targeting cancer dormancy based on direct target binding and engagement in live cancer cells. These compounds in combination with chemotherapeutic agents, have the potential to improve patient outcomes and prolong survival. Citation Format: Alexei Belenky, Alexandra Kuznetsova, Michael Frid, Felix Chapovsky, Marc Duey, Maria Vilenchik. Validation of drug candidates targeting dormant cancers in live cells as a key for successful translation into the clinic [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 5161.
Abstract 435: Mouse models of human cancer
Authors: Carol J. Bult, Debra M. Krupke, Steven B. Neuhauser, Joel E. Richardson, John P. Sundberg
Journal: Cancer Research (2020)

Abstract Mouse models play a crucial role in understanding the genetic and genomic basis of cancer and for the development of novel cancer therapies. Because data and information about these models are distributed and heterogeneous, gaining an appreciation for which models have been developed and what their characteristics are presents a major challenge for cancer researchers. The Mouse Models of Human Cancer Database (MMHCdb; http://tumor.informatics.jax.org) solves this challenge by providing a comprehensive, expertly curated on-line information resource about genetically engineered (GEMMs) and inbred mouse models of human cancer. In partnership with the European Bioinformatics Institute (EMBL/EBI), MMHCdb has also developed and implemented PDX Finder, a global catalog of Patient Derived Xenograft models (https://www.pdxfinder.org). Both MMHCdb and PDX Finder employ metadata standards to simplify the process of searching for relevant mouse models by diverse criteria including cancer type, type of strain, and genetic alteration. MMHCdb contains more than100,000 records on tumor frequency data for over 7,600 different mouse strains. These data are linked to over 4,700 references, 2,900 pathology reports, and 6,900 images. PDX Finder provides researchers with one stop access to information about more than 2,800 PDX models in repositories from around the world. MMHCdb and PDX Finder are supported, in part, by NIH/NCI CA089713. MMHCdb was formerly called the Mouse Tumor Biology database (MTB). Citation Format: Carol J. Bult, Debra M. Krupke, Steven B. Neuhauser, Joel E. Richardson, John P. Sundberg. Mouse models of human 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 435.
Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes
Authors: Zixi Wang, Kenian Chen, Yuemeng Jia, Jen-Chieh Chuang, Xuxu Sun, Yu-Hsuan Lin, Cemre Celen, Lin Li, Fang Huang, Xin Liu, Diego H. Castrillon, Tao Wang, Hao Zhu
Journal: Nature Cancer (2020)
A porcine ligated loop model reveals new insight into the host immune response against <i>Campylobacter jejuni</i>
Authors: Nicholas M Negretti, Yinyin Ye, Lais M Malavasi, Swechha M Pokharel, Steven Huynh, Susan Noh, Cassidy L Klima, Christopher R Gourley, Claude A Ragle, Santanu Bose, Torey Looft, Craig T Parker, Geremy Clair, Joshua N Adkins, Michael E Konkel
Journal: Gut Microbes (2020)

The symptoms of infectious diarrheal disease are mediated by a combination of a pathogen's virulence factors and the host immune system. Campylobacter jejuni is the leading bacterial cause of diarrhea worldwide due to its near-ubiquitous zoonotic association with poultry. One of the outstanding questions is to what extent the bacteria are responsible for the diarrheal symptoms via intestinal cell necrosis versus immune cell initiated tissue damage. To determine the stepwise process of inflammation that leads to diarrhea, we used a piglet ligated intestinal loop model to study the intestinal response to C. jejuni. Pigs were chosen due to the anatomical similarity between the porcine and the human intestine. We found that the abundance of neutrophil related proteins increased in the intestinal lumen during C. jejuni infection, including proteins related to neutrophil migration (neutrophil elastase and MMP9), actin reorganization (Arp2/3), and antimicrobial proteins (lipocalin-2, myeloperoxidase, S100A8, and S100A9). The appearance of neutrophil proteins also corresponded with increases of the inflammatory cytokines IL-8 and TNF-α. Compared to infection with the C. jejuni wild-type strain, infection with the noninvasive C. jejuni ∆ciaD mutant resulted in a blunted inflammatory response, with less inflammatory cytokines and neutrophil markers. These findings indicate that intestinal inflammation is driven by C. jejuni virulence and that neutrophils are the predominant cell type responding to C. jejuni infection. We propose that this model can be used as a platform to study the early immune events during infection with intestinal pathogens.
Abstract 1782: N-myristoyltransferase proteins in breast cancer: Prognostic relevance and validation as a new drug target
Authors: John R. Mackey, Justine Lai, Utkarsh Chauhan, Wei-Feng Dong, Darryl Glubrect, Sunita Ghosh, Gilbert Bigras, Raymond Lai, Luc G. Berthiaume
Journal: Cancer Research (2020)

Abstract N-myristoyltransferases (NMTs) catalyze the addition of 14-carbon fatty acids to the N-terminus of proteins. This activity regulates numerous membrane-bound signal transduction pathways important in cancer biology, and the pan-NMT inhibitor PCLX-001 is in clinical development as a cancer therapy. The physiologic distribution and relative contributions of the two human NMTs, NMT1 and NMT2, remain poorly understood as previous studies used polyclonal antibodies with potential cross-reactivity. We generated and validated mutually exclusive monoclonal antibodies (mAbs) specific to the human isotypes of NMT1 and NMT2. These mAbs were used to perform an immunohistochemical (IHC) analysis of the abundance and distribution of NMT1 and NMT2 in normal human breast epithelial samples and a large (n=703) cohort of primary breast adenocarcinomas from the BCIRG001 study. While NMT1 protein was readily identifiable in most normal and transformed breast epithelial tissue, NMT1 abundance was associated with higher overall histologic grade, higher Ki67, and lower hormone expression. While NMT2 protein was readily detected in normal breast epithelial tissue, NMT2 protein was undetectable in the majority of malignant breast cancers, but detectable NMT2 protein correlated with significantly poorer overall survival outcomes (hazard ratio for death 1.36; p &amp;lt; 0.029) and significantly worse biological features including younger age, higher histologic grade, lower hormone receptor expression, higher Ki67, and p53 positivity. NMT status was unrelated to HER2 status. NMT1 and NMT2 protein abundances were positively correlated with each other. Treatment of cultured breast cancer cells with the pan-NMT inhibitor PCLX-001 reduced cell viability in vitro. Daily oral administration of PCLX-001 to immunodeficient mice bearing human MDA-MB-231 breast cancer xenografts induced significant dose-dependent tumor growth inhibition in vivo. These results support the further evaluation of NMT immunohistochemistry for selection of patients for NMT inhibitor therapy, and clinical trials of NMT inhibition in breast cancer patients. Citation Format: John R. Mackey, Justine Lai, Utkarsh Chauhan, Wei-Feng Dong, Darryl Glubrect, Sunita Ghosh, Gilbert Bigras, Raymond Lai, Luc G. Berthiaume. N-myristoyltransferase proteins in breast cancer: Prognostic relevance and validation as a new drug target [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 1782.
THU0182 Significant reduction in serious upper gastrointestinal (ugi) events with celecoxib, a cox-2 specific inhibitor, compared with conventional nsaids. the success i trial
Authors: JL Goldstein, G Eisen, W Stenson, N Agrawal, AE Bello, JG Fort, SP Boots
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The Celecoxib Long-term Arthritis Safety Study (CLASS), a North American prospective outcomes study, demonstrated a significant reduction in UGI ulcer complications and improved tolerability. <h3>Objectives</h3> To extend our understanding of the UGI safety advantages of celecoxib over conventional NSAIDs, a naturalistic study was conducted worldwide. <h3>Methods</h3> SUCCESS I, a large, 12-week, multinational, prospective, double-blind, randomised trial in 13,274 osteoarthritis patients, was conducted in 39 countries. There were 6547 patients from Europe/Africa, 2756 from North America, 2889 from Latin America, and 1082 from Asia/Pacific. Celecoxib 200 mg/d (n = 4421) and 400 mg/d (n = 4429) was compared with naproxen 1000 mg/d (n = 914) and diclofenac 100 mg/d (n = 3510) with regard to UGI safety. Investigators were required to report all potential clinically significant UGI events and were allowed/requested to follow local standards of care with regard to work-up and treatment of events. Events data were collected prospectively. An independent Gastrointestinal Events Committee (GEC) reviewed all data in a blinded fashion. Events were categorised as UGI ulcer complications (perforations, gastric outlet obstruction, bleeding) or symptomatic UGI ulcerations (predefined as in CLASS). A total of 144 cases were reviewed and adjudicated by the GEC. <h3>Results</h3> See Table 1. <h3>Conclusion</h3> These data confirm CLASS results that celecoxib is associated with significantly fewer ulcer complications and symptomatic UGI ulcerations than conventional NSAIDs. The differences in event rates between SUCCESS and CLASS may relate to regional differences in surveillance or clinical practice. Sponsored by Pharmacia Corporation and Pfizer, Inc.