tbuckley/cabot-search huggingface dataset:
Abstract 4660: Chronic obstructive pulmonary disease as an independent risk factor for cancer
Authors: Joseph Finkelstein, Xingyue Huo
Journal: Cancer Research (2020)

Abstract Background: Low-grade systemic inflammation is considered a hallmark of chronic obstructive pulmonary disease (COPD) that potentially links COPD to increased cancer risk. However relationship between COPD and cancer remains controversial. The main purpose of this study was to assess the relationship between COPD and all-cause cancer among adult smokers in a nested case-control study. Methods: The study used the 2018 Behavioral Risk Factor Surveillance System (BRFSS) dataset. Only individuals of 40 years and older who smoked at least 100 cigarettes in their lifetime were included into analysis. A nested case-control design has been employed with COPD as an exposure and cancer as an outcome. Cases with COPD were matched at 1:1 ratio with controls without COPD by age group, race, and sex using simple random sampling. Chi-square test was applied to determine whether the prevalence of cancer in the resulting groups was statistically significantly different. Conditional logistic regression was used to estimate the association between cancer and COPD after adjusting for covariates (education, income, BMI, marital, drinking and exercise status). Results: Overall, 146,141 participants aged 40 or more who smoked at least 100 cigarettes in their entire lives were included into the study. 25,528 subjects with COPD were matched with non-COPD subjects by individual case-control matching at a 1:1 ratio. People who had COPD were more likely to report being diagnosed with cancer (OR=1.40, [95%CI, 1.32-1.48]) than non-COPD participants after adjusting for confounders. The result was similar in the original population (OR=1.39, [95%CI, 1.28-1.51]). Conclusion: Our findings demonstrate that the diagnosis of COPD was significantly associated with cancer among smokers who aged more than 40 years old. Citation Format: Joseph Finkelstein, Xingyue Huo. Chronic obstructive pulmonary disease as an independent risk factor for 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 4660.
We need a robust evidence base to unravel the relationship between sex hormones and asthma
Authors: Aziz Sheikh, Mome Mukherjee
Journal: Thorax (2020)

There has long been interest in whether sex hormones play a role in the development of asthma and influence its natural history, but much of this evidence base is of poor quality and hence difficult to interpret. This interest stems from clinical experiences, and findings from a substantial body of epidemiological investigations, and a smaller body of mechanistic and experimental studies. These have mainly focused on oestrogen and progesterone in females with inconsistent results. The focus on testosterone in both males and females in the linked study by Han et al is therefore welcome but other than these strengths,1 it suffers from many of the same limitations as much of the previous body of epidemiological work. In this editorial, we seek to contextualise the findings from Han et al and offer suggestions on how to strengthen the evidence base for understanding the relationship between sex hormones and asthma.

There is considerable circumstantial evidence implicating sex hormones in asthma. For example, it is widely recognised that asthma is more prevalent in boys in the prepubertal period and that these sex differences reverse after menarche until at least the time of the menopause.2 These sex differences are also seen in asthma admission patterns.3 There is in addition evidence that fluctuations in sex hormones associated with menstruation, pregnancy and menopause can influence some women’s asthma control.4 Furthermore, there …
System for High-Intensity Evaluation During Radiation Therapy (SHIELD-RT): A Prospective Randomized Study of Machine Learning–Directed Clinical Evaluations During Radiation and Chemoradiation
Authors: Julian C. Hong, Neville C. W. Eclov, Nicole H. Dalal, Samantha M. Thomas, Sarah J. Stephens, Mary Malicki, Stacey Shields, Alyssa Cobb, Yvonne M. Mowery, Donna Niedzwiecki, Jessica D. Tenenbaum, Manisha Palta
Journal: Journal of Clinical Oncology (2020)

Patients undergoing outpatient radiotherapy (RT) or chemoradiation (CRT) frequently require acute care (emergency department evaluation or hospitalization). Machine learning (ML) may guide interventions to reduce this risk. There are limited prospective studies investigating the clinical impact of ML in health care. The objective of this study was to determine whether ML can identify high-risk patients and direct mandatory twice-weekly clinical evaluation to reduce acute care visits during treatment.During this single-institution randomized quality improvement study (ClinicalTrials.gov identifier: NCT04277650), 963 outpatient adult courses of RT and CRT started from January 7 to June 30, 2019, were evaluated by an ML algorithm. Among these, 311 courses identified by ML as high risk (> 10% risk of acute care during treatment) were randomized to standard once-weekly clinical evaluation (n = 157) or mandatory twice-weekly evaluation (n = 154). Both arms allowed additional evaluations on the basis of clinician discretion. The primary end point was the rate of acute care visits during RT. Model performance was evaluated using receiver operating characteristic area under the curve (AUC) and decile calibration plots.Twice-weekly evaluation reduced rates of acute care during treatment from 22.3% to 12.3% (difference, -10.0%; 95% CI, -18.3 to -1.6; relative risk, 0.556; 95% CI, 0.332 to 0.924; P = .02). Low-risk patients had a 2.7% acute care rate. Model discrimination was good in high- and low-risk patients undergoing standard once-weekly evaluation (AUC, 0.851).In this prospective randomized study, ML accurately triaged patients undergoing RT and CRT, directing clinical management with reduced acute care rates versus standard of care. This prospective study demonstrates the potential benefit of ML in health care and offers opportunities to enhance care quality and reduce health care costs.
Abstract 6611: Functional characterization of a novel gene in the antigen presentation pathway allows specific immunotherapeutic targeting of glioblastoma cancer stem cells
Authors: Reilly L. Kidwell, Xiqing Li, Jeremy N. Rich
Journal: Cancer Research (2020)

Abstract Glioblastoma is the most prevalent and aggressive primary brain tumor in adults, and conventional treatment strategies have made minimal progress in prolonging overall survival. Cancer stem cells are critical for tumor initiation, growth, and maintenance, and are able to co-opt complex host mechanisms to evade immune recognition. Immune checkpoint inhibition has proven revolutionary for the treatment of several types of solid tumors, but has largely failed in attempts to improve outcomes in glioblastoma. Developing a deeper understanding of the functional immunomodulatory role of genes unique to glioma stem cells (GSCs) may help to elucidate this enigma, and inform more specific immunotherapeutic targeting. To better understand the ability of GSCs to promote immunosuppression and self-tolerance in the tumor niche, we interrogated RNA-seq data from GSCs and differentiated glioma cells (DGCs) and identified a novel gene in the antigen presentation pathway (APP). In vitro targeting of this gene increased sensitivity to CD8+ T cell killing and reduced expression of other T-cell inhibitory ligands in GSCs alone, decreasing tumor-mediated immunosuppression. Compared to DGCs, GSCs were found to be key promoters of immune self-tolerance and evasion, with unaltered GSCs exhibiting minimal peptide binding to MHC Class I and, therefore, decreased antigen presentation. Specific targeting of the identified APP gene led to a reversal of this interaction, with increased binding capacity and, correspondingly, tumor antigen recognition. In vivo administration of a specific APP gene targeting agent in human GSC xenograft mice displayed decreased tumor burden and a striking prolongation of overall survival compared to both controls and mice treated with known immune checkpoint inhibitors. High expression of the APP gene is associated with poor clinical prognosis, supporting the clinical relevance of this discovery. Thus, novel targeting of the antigen-presenting pathway may provide a therapeutic vulnerability unique to glioblastoma cancer stem cells. Citation Format: Reilly L. Kidwell, Xiqing Li, Jeremy N. Rich. Functional characterization of a novel gene in the antigen presentation pathway allows specific immunotherapeutic targeting of glioblastoma cancer stem cells [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 6611.
Abstract 4543: Phenotypic screening of bispecific antibodies in 3D tumor immune cell cocultures
Authors: Lidia Daszkiewicz, Gera Goverse, Nataliia Beztsinna, Benjamin Visser, Lois van der Drift, Kuan Yan, Leo Price
Journal: Cancer Research (2020)

Abstract INTRODUCTION The co-culture of tumor and immune cells in 3D enables a better recapitulation of the complex interactions between cells and the tumor microenvironment. High content analysis can be used to evaluate the effects of diverse immunotherapeutics on anti-tumor immune responses in a 3D setting. Functional read-outs can include active migration of immune cells towards tumoroids, infiltration of immune cells into the tumoroids and tumor killing. Here, we have applied high content analysis to quantify the effects of bi-specific antibodies targeting both the tumor and the T cells in 3D culture in a 384 well plate format. MATERIAL and METHODS Tumoroids generated from various cancer cell types were cultured in 3D in an extracellular matrix-rich protein hydrogel. Partially HLA-matching T cells isolated from healthy PBMCs donors were added with or without activation to the 3D culture and their infiltration into tumoroids and subsequent killing was visualized using high-content microscopy. Quantification of effects on immune cells and tumoroids was achieved with morphometric analysis with OMinerTM software. RESULTS and DISCUSSION Image-based analysis enabled the assessment of tumor-immune cell interactions and tumor killing in 3D co-cultures. The activation status of T cells determined the level of immune cell infiltration and killing of the tumoroids. T cell engaging bi-specific antibodies enhanced infiltration and tumor killing and was associated with increased IFNγ levels in culture supernatants. CONCLUSION Here we demonstrated the enhanced immune cell infiltration and tumor killing induced by bi-specific antibodies that simultaneously engage both T cells and tumors in a 3D setting. This assay represents a more physiologically relevant approach to enable cancer immunotherapy drug developers to evaluate the activity of novel immunotherapeutic molecules and better understand their mechanism of action. Citation Format: Lidia Daszkiewicz, Gera Goverse, Nataliia Beztsinna, Benjamin Visser, Lois van der Drift, Kuan Yan, Leo Price. Phenotypic screening of bispecific antibodies in 3D tumor immune cell cocultures [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 4543.
Abstract 5854: New therapeutic targets of ER positive breast cancer are revealed through nascent RNA transcription time series
Authors: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka
Journal: Cancer Research (2020)

Abstract Mechanistic understanding of Estrogen Receptor (ER) signaling will lead to new therapeutic targets for ER positive breast cancer. To this end, Arpeggio performed nascent RNA sequencing following estradiol (E2) treatment in MCF7 breast cancer cells every 15 minutes for 6 hours. To date, our study represents the densest time series of estrogen signaling ever reported. Arpeggio noted three transcriptional waves following E2 treatment: peaks at 30 minutes, 2.5 hours and 5 hours, respectively. We noted that the early response was enriched for canonical ER signaling, however, mid and late response were enriched for metabolic processes. Because our study was statistically powered with 24 time points, we could use delay-coordinate embedding to look for causal gene interactions. We implicated NME2 as the causal driver of the 5-hour transcriptional wave. Indeed, NME2 and Estrogen Receptor (ER) have been shown to co-localize where NME2 blocks ER effect. Our study represents a new methodology for target discovery in hormone-driven cancers. Citation Format: Joseph Azofeifa, Joel Basken, Maria Lai, Ryan Langendorf, Laura Norris, Tim Read, Adam Robbins-Pianka. New therapeutic targets of ER positive breast cancer are revealed through nascent RNA transcription time series [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 5854.
Abstract 5066: Investigating the role of IL-6 to modulate the immunosuppressive tumor microenvironment of EGFR mutant NSCLC
Authors: Sonia A. Patel, Monique Nilsson, Sungnam Cho, Xiuning Le, John Heymach
Journal: Cancer Research (2020)

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death with a less than 15% five-year survival. Approximately 15% of NSCLC cases in the US harbor epidermal growth factor receptor (EGFR) activating mutations and are initially highly sensitive to EGFR tyrosine kinase inhibitors (TKI). Unfortunately, the vast majority of tumors acquire EGFR TKI resistance, and treating resistant disease remains a clinical challenge. Additional therapeutic modalities, such as immunotherapy, are needed to improve clinical outcome. While immunotherapy has shown clinical activity in multiple cancer types including NSCLC, a lack of efficacy has been observed in EGFR mutant NSCLC patients. The biological mechanisms driving immunotherapy resistance in EGFR mutant NSCLC are not well understood, and additional EGFR mutant NSCLC patients. We previously reported that IL-6 is upregulated in NSCLC cells with acquired resistance to EGFR TKIs. Given the role of IL-6 as an immunomodulatory cytokine, we evaluated the effects of IL-6 signaling on immunosuppression in genetically engineered mouse models (GEMMs) of EGFR mutant NSCLC. IL-6 knockout (EGFRL858R/IL-6KO) resulted in decreased PD-L1 expression on the surface of EGFR mutant tumor cells compared to tumors in IL-6 proficient mice. Additionally, we observed a modest increase in PD-1 expression on CD8+ T cells in EGFRL858R/IL-6KO mice compared to EGFRL858R mice, suggesting that IL-6 acts on both tumor and immune populations to facilitate a “cold” immunosuppressive tumor microenvironment. We next analyzed immune populations in EGFR mutant tumors from mice with or without knockout of IL-6 by single cell RNA sequencing and validated these findings by immunohistochemistry. Tumors in EGFRL858R/IL-6KO mice displayed decreased B-cell (CD20) populations, increased macrophages (F480), and increased natural killer cells (NKp46) compared to tumors from IL-6 expressing EGFRL858R mice. Our data suggests that the increased expression of IL-6 in EGFR TKI resistant NSCLC may alter immune cell populations within the tumor microenvironment and impact immunosuppression, and that therapeutic approach targeting IL-6 merit further investigation for EGFR-mutant NSCLC. Citation Format: Sonia A. Patel, Monique Nilsson, Sungnam Cho, Xiuning Le, John Heymach. Investigating the role of IL-6 to modulate the immunosuppressive tumor microenvironment of EGFR mutant NSCLC [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 5066.
Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression
Authors: Jesse W. Williams, Konstantin Zaitsev, Ki-Wook Kim, Stoyan Ivanov, Brian T. Saunders, Patricia R. Schrank, Kyeongdae Kim, Andrew Elvington, Seung Hyeon Kim, Christopher G. Tucker, Mary Wohltmann, Brian T. Fife, Slava Epelman, Maxim N. Artyomov, Kory J. Lavine, Bernd H. Zinselmeyer, Jae-Hoon Choi, Gwendalyn J. Randolph
Journal: Nature Immunology (2020)
Prevalence of Third-Party Tracking on COVID-19–Related Web Pages
Authors: Matthew S. McCoy, Timothy Libert, David Buckler, David T. Grande, Ari B. Friedman
Journal: JAMA (2020)

This study uses webXray, an automated tool that detects tracking on websites, to describe the prevalence and characteristics of third-party data requests and cookies on the top 20 COVID-19–related websites, including academic and government sites, from US-based search results in May 2020.
Abstract LB-107: <i>TET2</i>/<i>DNMT3A</i> mutations and exceptional response to novel epigenetic agent in human malignancies
Authors: Sherry X. Yang, Larry Rubinstein, Dat Nguyen, Angelo B. Larenjeira, Robert Kinders, Michael Difilippantonio, James H. Doroshow
Journal: Cancer Research (2020)

Abstract Background: Challenges remain on the selection of patients who potentially respond to a class of drugs that target the epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations, their role on prognosis, and relation between the mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. Methods: TET2/DNMT3A mutation data in human malignancies were obtained from cBioPortal. Eighteen cancer cell lines and multiple mouse models bearing representative human solid tumors were subjected to 4'-thio-2'-deoxycytidine (T-dCyd) or saline treatment. Gene mutations were examined by whole exome and/or Sanger sequencing in these cell lines. Pharmacodynamic modulation of specific gene expression was analyzed in xenograft tumor samples by immunohistochemistry. Results: TET2 and DNMT3A were frequently mutated in angioimmunoblastic/peripheral T-cell lymphomas, several types of leukemias and cutaneous squamous cell carcinoma, and mutated in lung, breast, skin, and kidney cancers. T-dCyd significantly reduced cell survival in lung NCI-H23, breast BT549, melanoma SKMEL5 and renal ACHN cancer cells that harbor deleterious TET2 and nonsynonymous DNMT3A mutations compared to 14 lines without such pattern of alterations (P = 0.006; 2-sided T-test). Anti-tumor effect was validated in vivo; T-dCyd significantly inhibited tumor growth in mice with TET2/DNMT3A mutation-positive tumors. Histological evaluation revealed a near eradication of tumor cells by T-dCyd in NCI-H23 xenografts. T-dCyd administrations led to a remarkable and persistent p21Waf1/Cip1 increase during treatment (P &amp;lt; 0.0001). In contrast, little activity was observed in xenograft models without this pattern of gene mutations. Conclusions: Cancer cells and animal models examined with TET2 and DNMT3A-mutant genotype are sensitive to T-dCyd treatment. Citation Format: Sherry X. Yang, Larry Rubinstein, Dat Nguyen, Angelo B. Larenjeira, Robert Kinders, Michael Difilippantonio, James H. Doroshow. TET2/DNMT3A mutations and exceptional response to novel epigenetic agent in human malignancies [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-107.
Abstract 3361: Discovery and preclinical characterizations of a humanized anti-claudin 18.2 antibody SPX-101
Authors: Guidong Zhu, Jichun Ma, Jingdong Ye, Jingdong Qin, Yi Cai
Journal: Cancer Research (2020)

Abstract Claudin 18.2 (CLDN 18.2) is a major component of the tight junctions and is highly expressed in several cancers including gastric (80%), esophageal (80%), pancreatic (60%) and lung cancers, but only expressed at very low levels in healthy tissues. The chimeric IgG1 CLDN 18.2 antibody zolbetuximab significantly improved PFS and OS in gastric cancer patients in a CLDN 18.2-dependent manner on the background of EOX. This research aimed to produce humanized anti-claudin18.2 antibodies with enhanced activities and improved pharmaceutical characteristics compared to known CLDN 18.2 antibodies. We used several immunization methods to produce mouse anti-CLDN18.2 antibodies with high affinity and excellent selectivity against CLDN 18.1. Humanization of a selected clone led to a humanized anti-CLDN18.2 antibody (h533o) with significantly improved binding affinity and cellular activity in ADCC and CDC assays compared to zolbetuximab. The binding affinity of h533o was relatively insensitive to elevated temperatures or acidity, suggesting the robustness of target engaging ability in tumor microenvironment. Maturation and selection by the off-rate approach, using phage libraries that systematically modified the CDR regions, identified multiple antibodies with comparable affinity and selectivity. Mutational scan of the Fc region in h533o identified SPX-101 with reduced ADA effect in mice while retaining other favorable properties. SPX-101 suppressed tumor growth in several xenograft mouse models including NUGC4 and HEK293 cells that stably expressed CLDN18.2. In summary, SPX-101 represents a humanized anti-CLDN18.2 antibody with high affinity and specificity, high effector cell-mediated cytotoxicity, low immunogenicity, and in vivo tumor control efficacy in xenograft rodent models. Citation Format: Guidong Zhu, Jichun Ma, Jingdong Ye, Jingdong Qin, Yi Cai. Discovery and preclinical characterizations of a humanized anti-claudin 18.2 antibody SPX-101 [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 3361.