tbuckley/cabot-search huggingface dataset:
Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction
Authors: Christopher D. Pascoe, Aruni Jha, Min Hyung Ryu, Mirna Ragheb, Jignesh Vaghasiya, Sujata Basu, Gerald L. Stelmack, Sadeesh Srinathan, Biniam Kidane, Jason Kindrachuk, Paul M. O'Byrne, Gail M. Gauvreau, Amir Ravandi, Christopher Carlsten, Andrew J. Halayko
Journal: European Respiratory Journal (2020)

Oxidised phosphatidylcholines (OxPCs) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored. The aim of this study was to characterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild asthma. The capacity of OxPCs to contribute to pathobiology associated with asthma was also to be determined. Using bronchoalveolar lavage fluid from two human cohorts, OxPC species were quantified using ultra-high performance liquid chromatography-tandem mass spectrometry. Murine thin-cut lung slices were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks. OxPC profiles in the airways were different between people with and without AHR and correlated with methacholine responsiveness. Exposing patients with mild asthma to allergens produced unique OxPC signatures that associated with the severity of the late asthma response. OxPCs dose-dependently induced 15% airway narrowing in murine thin-cut lung slices. In HASM cells, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, interleukin (IL)-6, IL-8, granulocyte−macrophage colony-stimulating factor and the production of oxylipins via protein kinase C-dependent pathways. Data from human cohorts and primary HASM cell culture show that OxPCs are present in the airways, increase after allergen challenge and correlate with metrics of airway dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.
Abstract 5031: <i>Salmonella</i>-mediated suppression of Akt/mTOR signaling inhibits metastasis via downregulation of Snail expression in melanoma
Authors: Christian R. Pangilinan, Che-Hsin Lee
Journal: Cancer Research (2020)

Abstract The expression of EMT inducer Snail in many cancer types has been implicated in high-grade malignancies and correlated with poor prognosis. Tumor-intrinsic Snail not only has direct effects on metastasis but also impacts tumor microenvironment by altering secretomes. Our previous reports demonstrated that systemic administration of Salmonella significantly reduced tumor growth and metastatic nodules of tumor-bearing mice, in part, by coaxing changes in the tumor microenvironment. These led us to hypothesize that Salmonella targets metastasis inducers. Here, we use B16F10 and K1735 mouse melanoma cells to investigate the anti-metastatic potentials of Salmonella against melanoma. Immunoblotting revealed that the expression of Snail in both B16F10 and K1735 melanoma cell lines was significantly downregulated following Salmonella treatment in a dose-dependent manner. Likewise, the phosphorylation of Akt and mTOR was significantly reduced after Salmonella treatment. Our findings further revealed that in vitro metastatic activities of Salmonella-treated melanoma cells were significantly inhibited as demonstrated in the wound-healing and Transwell assays. When transfected with constitutively active AKT plasmid, B16F10 and K1735 markedly increased the phosphorylation of Akt and mTOR accompanied by an elevated Snail expression. Interestingly, Salmonella treatment reversed the Akt/mTOR and Snail upregulation of cells overexpressing Akt. Our data therefore suggest that Salmonella significantly reduces melanoma metastasis by downregulating Snail. Citation Format: Christian R. Pangilinan, Che-Hsin Lee. Salmonella-mediated suppression of Akt/mTOR signaling inhibits metastasis via downregulation of Snail expression in melanoma [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 5031.
THU0016 Sialic acid, intercellular adhesion molecule-1 and rheumatoid arthritis: a study on the erythrocyte membrane
Authors: S Cogalgil, F Akcay, S Karatay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> We aimed to measure serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and erythrocyte membrane sialic acid (SA) activity and the correlation of these parameters in patients with rheumatoid arthritis (RA), and to investigate the correlation of these parameters with the disease activity. <h3>Methods</h3> Serum sICAM-1 levels were determined with sandwich enzime-linked immunosorbent assay (ELISA) and SA concentration was determined according to the method of Shamberger in sera from 42 patients with RA and in 30 healthy controls. Erythtrocyte sedimentation rate (ESR) was determined according to the Westhergen method and C-reactive protein (CRP) by nephelometric method. Disease activity was assessed by disease activity criterias. <h3>Results</h3> Significantly lower erythrocyte membrane SA and higher serum levels of sICAM-1 were found in patients with RA than in healthy controls (p &lt; 0.001 for both). Significant negative correlation between sICAM-1 level and erythyrocyte membrane SA concentration (r = ?0.49, p &lt; 0.001), and positive correlation between sICAM level with Ritche articular index (RAI) score and CRP (r = 0.32, p &lt; 0.05; r = 0.44, p &lt; 0.01, respectively), were observed. No significant correlation was found between sICAM-1 level with ESR, age and disease duration. There was not any correlation between values of CRP, RAI score and ESR with erythrocyte membrane SA concentration. <h3>Conclusion</h3> From these data, it is concluded that decreases in erythrocyte membrane SA concentration and increases in sICAM-1, ESR and CRP levels are present in RA, and that the decrease in erythrocyte membrane SA concentration in RA might be due to increased sICAM-1, and increased levels of sICAM-1 and correlations with other parameters may be a significant and novel marker for evaluating the disease status and the activity of RA.
Abstract 4014: Measuring direct binding to epigenetic targets using SPR
Authors: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma
Journal: Cancer Research (2020)

Abstract Epigenetic modifications are dynamic and reversible processes that regulate gene expression without altering the underlying sequence of the DNA. Gene expression is instead controlled by chromatin modifications, such a DNA methylation, histone modification, and chromatin remodeling. Proteins involved in epigenetic modifications are categorized as writers, which modify the chromatin; readers, that recognize the modifications; and erasers which remove the modifications. While essential for cellular function, abnormal expression or alteration of the proteins involved in epigenetic regulation leads to diseases, such as cancer. Due to their role in disease, epigenetic modifiers are attractive targets for the discovery and development of novel therapeutics. Research in the field has shown many epigenetic proteins are druggable and several FDA-approved drugs have already been developed (Ref. 1). At Reaction Biology we offer a suite of services for epigenetic drug discovery, including the largest panel for epigenetic screening and profiling in the industry with over 30 Methyltransferases, 100+ Reader Domain Proteins, HATs, HDACs, Demethylases, DUBs, PARPs, and more. In order to directly probe the strength of the binding interaction between the epigenetic target and potential therapeutics we offer biophysical assays, such as surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and microscale thermophoresis (MST). Here we present SPR binding data for three epigenetic targets: NSD2 (writer), PRMT5 (writer), and Bromodomain-4 (reader). Through the use of commercially available controls, we developed SPR assays for these targets that can be used to screen compound or fragment libraries, determine kinetics/affinity, and profile binding specificity. (Ref 1.) V. Prachayasittikul et al (2017) Exploring the epigenetic drug discovery landscape. Expert Opin. Drug Discov. 12(4): 345-362. Citation Format: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma. Measuring direct binding to epigenetic targets using SPR [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 4014.
Abstract A51: The role of ATF6-mediate AP-1 signaling in promoting PARP inhibitor-resistant ovarian cancer
Authors: Alexandra N. McMellen, Benjamin G. Bitler
Journal: Clinical Cancer Research (2020)

Abstract The purpose of this study is to define the role of AP-1 mediated DNA repair in PARP inhibitor (PARPi)-resistant high-grade serous ovarian cancer (HGSOC). AP-1 is a dimeric transcription factor comprising Jun, Fos, and/or ATF proteins and its signaling is known to regulate multiple DNA repair genes, including PARP1. Wnt activation can promote AP-1 signaling and upregulates expression of AP-1 subunits. We previously published that hyperactive Wnt signaling in PARPi-resistant HGSOC cells promotes DNA repair and attenuates PARPi response. We therefore hypothesized that Wnt signaling drives PARPi resistance thorough increased AP1-signaling and subsequent enhanced DNA repair. We performed transcription factor analysis of RNA sequencing data from TP53/BRCA2-mutated olaparib-sensitive (PEO1) and -resistant (PEO1-OR) HGSOC cells. We observed increased AP-1 target genes in resistant cells and confirmed elevated AP-1 activity with a reporter assay. Quantitative PCR (qPCR) demonstrated that a majority of AP-1 subunits were upregulated in olaparib-resistant cells, namely JUN, ATF5, and ATF6. An shRNA screen was performed to determine which AP-1 subunits are necessary to convey olaparib resistance. Four out of five shRNAs targeting ATF6 effectively resensitized PARPi-resistant cells to olaparib. We confirmed that ATF6 protein was elevated in PEO1-OR cells. To further explore the role of ATF6 in AP-1 mediated PARPi resistance, ATF6 was stably knocked down in PEO1-OR cells. Colony formation assays confirmed that loss of ATF6 resensitized cells to olaparib. Knockdown of ATF6 also resulted in decreased transcription of PARP1, as measured by qPCR, and higher baseline levels of DNA damage, as measured by phosphorylated histone gamma-H2AX. Future studies will evaluate ATF6-dependent DNA repair in in vitro and in vivo models of PARPi-resistant HGSOC. In summary, these data indicate activation of AP-1 signaling through increased expression of ATF6 is promoting enhanced DNA repair capacity, which could be contributing to PARPi resistance. Thus, pharmacologic inhibition of AP-1 or ATF6 could provide a targetable approach to overcome resistance and improve patient outcomes. Citation Format: Alexandra N. McMellen, Benjamin G. Bitler. The role of ATF6-mediate AP-1 signaling in promoting PARP inhibitor-resistant ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A51.
Abstract 3083: Selective inhibition of transcription factor BRN2 as a treatment strategy for Small Cell Prostate Cancer
Authors: Daksh Thaper, Ravi Munuganti, Adeleke Aguda, Soojin Kim, Shungyu Ku, Sahil Kumar, Sepideh Vahid, Shaghayegh Nouruzi, Olena Sivak, Dwaiyapan Ganguli, Colm Morrissey, Eva Corey, Himisha Beltran, Amina Zoubeidi
Journal: Cancer Research (2020)

Abstract Introduction: Resistance to newly developed androgen receptor pathway inhibitors (ARPIs), such as Enzalutamide (ENZ), rapidly emerges. In particular, a subset of patients who relapse following ARPI therapy their dependence on AR signaling and emerge with neuroendocrine features. These tumors, termed treatment induced small-cell prostate cancer (t-SCPC) or neuroendocrine prostate cancer (t-NEPC), carry an extremely poor prognosis and, to date, treatment remains decades old cytotoxic chemotherapies. Previously, our group identified the neural transcription factor BRN2 as a major clinically relevant driver of SCPC and now report that targeting BRN2 is a promising strategy to prevent neuroendocrine differentiation or treat NEPC.Methods/Results: In silico screening of small molecules was conducted on a model of BRN2 which was later validated with the first-in-field crystal structure of BRN2 DNA binding domain. On the basis of the model, several small molecules were identified that showed direct binding to BRN2 and inhibited its activity. Pharmacokinetic studies measured stability and bioavailability of med-chem optimized lead compound (BRN2i) that significantly reduced tumor growth in multiple xenograft models with no measurable side-effects. In silico modeling predicted a 7Å “closing” in the DBD once it was bound to BRN2i, this shift translated to reduced interaction with DNA by chromatin fractionation and ChIP-seq, thus confirming the mode of action for BRN2i is through loss of DNA binding. Loss of BRN2 binding reduced cell proliferation in tSCPC cell line 42DENZR, de novo SCPC cell line NCI-H660 and NEPC organoids as well as downregulated several known targets like EZH2, ASCL1, SOX2 and PEG10. Down-regulation of these target genes was also measured in the xenograft tumors, confirming on target effect in vivo. Moreover, the specificity of BRN2i was validated with CRISPR/Cas9 mediated knockout of BRN2 with downstream mRNA expression and phenotypic changes. Conclusion: The described work aims to lay the pre-clinical foundation for the integration of BRN2 targeted therapies into the treatment landscape to improve survival for patients suffering from small-cell neuroendocrine prostate cancer. Citation Format: Daksh Thaper, Ravi Munuganti, Adeleke Aguda, Soojin Kim, Shungyu Ku, Sahil Kumar, Sepideh Vahid, Shaghayegh Nouruzi, Olena Sivak, Dwaiyapan Ganguli, Colm Morrissey, Eva Corey, Himisha Beltran, Amina Zoubeidi. Selective inhibition of transcription factor BRN2 as a treatment strategy for Small Cell Prostate 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 3083.
Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters
Authors: Lisa H. Tostanoski, Frank Wegmann, Amanda J. Martinot, Carolin Loos, Katherine McMahan, Noe B. Mercado, Jingyou Yu, Chi N. Chan, Stephen Bondoc, Carly E. Starke, Michael Nekorchuk, Kathleen Busman-Sahay, Cesar Piedra-Mora, Linda M. Wrijil, Sarah Ducat, Jerome Custers, Caroline Atyeo, Stephanie Fischinger, John S. Burke, Jared Feldman, Blake M. Hauser, Timothy M. Caradonna, Esther A. Bondzie, Gabriel Dagotto, Makda S. Gebre, Catherine Jacob-Dolan, Zijin Lin, Shant H. Mahrokhian, Felix Nampanya, Ramya Nityanandam, Laurent Pessaint, Maciel Porto, Vaneesha Ali, Dalia Benetiene, Komlan Tevi, Hanne Andersen, Mark G. Lewis, Aaron G. Schmidt, Douglas A. Lauffenburger, Galit Alter, Jacob D. Estes, Hanneke Schuitemaker, Roland Zahn, Dan H. Barouch
Journal: Nature Medicine (2020)

Abstract Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death 1–4 . Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters 5–7 and nonhuman primates 8–10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates 11–13 . Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis.
Personal use of permanent hair dyes and cancer risk and mortality in US women: prospective cohort study
Authors: Yin Zhang, Brenda M Birmann, Jiali Han, Edward L Giovannucci, Frank E Speizer, Meir J Stampfer, Bernard A Rosner, Eva S Schernhammer
Journal: BMJ (2020)

Abstract Objective To evaluate the associations between personal use of permanent hair dyes and cancer risk and mortality. Design Prospective cohort study. Setting and participants 117 200 women enrolled in the Nurses’ Health Study, an ongoing prospective cohort study of female nurses in the United States. The women were free of cancer at baseline, reported information on personal use of permanent hair dyes, and were followed for 36 years. Exposure Status, duration, frequency, and integral use (cumulative dose calculated from duration and frequency) of permanent hair dyes. Age at first use and time since first use of permanent hair dyes. Main outcome measures Associations of personal use of permanent hair dyes with risk of overall cancer and specific cancers, and cancer related death. Age and multivariable adjusted hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazard models. Results Ever users of permanent hair dyes had no significant increases in risk of solid cancers (n=20 805, excluding non-melanoma skin cancers; hazard ratio 0.98, 95% confidence interval 0.96 to 1.01) or hematopoietic cancers overall (n=1807; 1.00, 0.91 to 1.10) compared with non-users. Additionally, ever users did not have an increased risk of most specific cancers (cutaneous squamous cell carcinoma, bladder cancer, melanoma, estrogen receptor positive breast cancer, progesterone receptor positive breast cancer, hormone receptor positive breast cancer, brain cancer, colorectal cancer, kidney cancer, lung cancer, and most of the major subclasses and histological subtypes of hematopoietic cancer) or cancer related death (n=4860; 0.96, 0.91 to 1.02). Basal cell carcinoma risk was slightly increased for ever users (n=22 560; 1.05, 1.02 to 1.08). Cumulative dose was positively associated with risk of estrogen receptor negative breast cancer, progesterone receptor negative breast cancer, hormone receptor negative breast cancer, and ovarian cancer. An increased risk of Hodgkin lymphoma was observed only for women with naturally dark hair (based on 70 women, 24 with dark hair), and a higher risk of basal cell carcinoma was observed for women with naturally light hair. Conclusion No positive association was found between personal use of permanent hair dye and risk of most cancers and cancer related mortality. The increased risk of basal cell carcinoma, breast cancer (estrogen receptor negative, progesterone receptor negative, hormone receptor negative) and ovarian cancer, and the mixed findings in analyses stratified by natural hair color warrant further investigation.
Abstract 2497: Topological data analysis revealed complexity behind ER positive breast cancer subtypes in TCGA transcriptome data
Authors: Takahiko Koyama, Aldo G. Saenz, Laxmi Parida
Journal: Cancer Research (2020)

Abstract Introduction: Breast cancer subtyping is still not fully agreed among oncologists. Today, many guidelines separate patients into four subtypes, luminal A, luminal B, Her2 positive, and triple negative breast cancers. However, distinction between luminal A and luminal B cases is not clear cut although many use Ki67 index. As more treatment options including immune checkpoint blockade are available, it is imperative to define strata and to find optimum treatments for each stratum. Method: TCGA BRCA transcriptome data (BRCA-UQ) is used, which has a sample size of 1089. We employed topological data analysis (TDA) which can handle high dimensional nature of transcriptome data in elegant manner. For characterization of the clusters, we used clinical data such as metastasis status, tumor sizes, age of diagnosis, survival, and pathological data and molecular data including PIK3CA, TP53, GATA3 mutations, MYC amplification, 8p23.2 deletion, 16q24.3 deletion, and tumor mutation burden (TMB). In addition, state of tumor microenvironment is assessed using CD45 expression for tumor infiltrating leukocytes (TIL) and HOXD12 expression for cancer associated fibroblast (CAF). Results: TDA cleanly clustered breast cancer transcriptome data separating ER+, Her2+ and triple negative cases. However, among ER+ cases, boundary between Luminal A and Luminal B is vague except for ER+/Her2+ cases. In ER+ cases, there are four clusters with poor prognosis. One has PIK3CA mutation, high MYC, and low TIL. Another cluster is characterized by GATA3 mutations. The other has low TIL and PIK3CA mutations. Also, high CAF cluster coincides with poor prognosis ones. Conclusions: The study revealed complexity behind ER+ breast cancer stratification from molecular and clinical perspectives. A TDA based method will likely to classify a patient into a right stratum better than conventional methods. Identified clusters with high TIL and high TMB which are good candidates for immune checkpoint blockade. Further study on identification of optimal treatments for each stratum will be warranted. Citation Format: Takahiko Koyama, Aldo G. Saenz, Laxmi Parida. Topological data analysis revealed complexity behind ER positive breast cancer subtypes in TCGA transcriptome data [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 2497.