tbuckley/cabot-search huggingface dataset:
Abstract 2368: Domatinostat increases apoptosis, G2M cell-cycle arrest and immunogenicity of Merkel cell carcinoma
Authors: Lina Song, Anne Catherine Bretz, Jan Gravemeyer, Ivelina Spassova, Svetlana Hamm, Shakhlo Muminova, Rene Bartz, Juergen C. Becker
Journal: Cancer Research (2019)

Abstract Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer prevalent in elderly and immunocompromised patients. MCC is highly immunogenic as it is either associated with Merkel cell polyoma virus (MCPyV) integration or UV-associated mutations in non-viral cases. Indeed, immune checkpoint inhibitors (CPI) like PD-1/PD-L1 blocking antibodies exert a strong clinical activity; however, primary or secondary resistance often occurs. Domatinostat (4SC-202) is an orally available small molecule inhibitor targeting histone deacetylases (HDAC) class I currently in clinical evaluation to improve response to CPI (SENSITIZE, NCT03278665). In syngeneic tumor mouse models domatinostat treatment demonstrated immune-modulatory effects by increasing the intra-tumoral infiltration of cytotoxic CD8+ T cells (CTLs) and enhancing gene expression of a CPI response signature. Immune escape mechanisms described for MCC include low intra-tumoral levels of CTLs and reduced expression of antigen-presenting MHC class I molecules. Our previous data suggest that low MHC-I levels are reversible and involve epigenetic silencing of genes encoding the antigen-processing machinery (APM). Here, we present novel preclinical data about the efficacy and mode of action of domatinostat in MCC. Global gene expression by single cell RNA-seq revealed regulation of genes involved, among others, in apoptosis and antigen presentation. Importantly, domatinostat additionally inhibited proliferation of MCC cell lines by induction of a G2M cell-cycle arrest and apoptosis. Moreover, expression of MCPyV-encoded transforming early genes, particularly during the G1-phase, was inhibited by domatinostat. Thus, it exerts also a direct anti-tumoral effect. In viable cells, domatinostat increases their susceptibility to immune responses, as qPCR and immunoblot analysis confirmed the induction of APM and MHC-I expression by domatinostat. APM and MHC-I expression has been reported to be restored by an epigenetic drug combination (vorinostat plus mithramycin). In contrast, we now provide evidence that the single agent treatment with domatinostat alone is sufficient for increasing immunogenicity of MCC cells. In summary, domatinostat counteracts immune escape of MCC in many aspects suggesting a combination treatment of the HDACi domatinostat with CPI as a promising therapeutic strategy. Prospective clinical trials are needed to confirm this hypothesis. Citation Format: Lina Song, Anne Catherine Bretz, Jan Gravemeyer, Ivelina Spassova, Svetlana Hamm, Shakhlo Muminova, Rene Bartz, Juergen C. Becker. Domatinostat increases apoptosis, G2M cell-cycle arrest and immunogenicity of Merkel cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2368.
Abstract MP48: Whole Grain Intake is Inversely Associated with Mortality From All Causes, Cardiovascular Disease, and Cancer in a Dose-response Manner, a Meta-analysis of Prospective Cohort Studies
Authors: Geng Zong, Alisa Gao, Frank Hu, Qi Sun
Journal: Circulation (2016)

Introduction: Whole grain intake has been associated with lower risks of multiple chronic conditions, but its association with mortality warrants further evaluation. Hypothesis: We performed a meta-analysis of prospective cohort studies on the association of whole grain intake with all-cause and cause-specific mortality, and tested the hypothesis that they followed inverse dose-response pattern. Methods: Published studies reporting relative risks (RRs) between whole grain consumption and mortality from Medline and Embase through August, 2015. Original results from National Health and Nutrition Examination Survey (NHANES) III and NHANES 1999-2004 were included. Whole grain ingredients (gram/day) were estimated among studies reporting RRs for ≥3 categories of whole grain intake. Results: Fourteen unique analyses were included, which consisted of 786,076 participants, 97,867 all-cause deaths, 23,957 CVD deaths, and 37,492 cancer deaths. Pooled RRs (95% confidence intervals) comparing high with low whole grain categories were 0.84 (0.80, 0.88; P &lt;0.001, I2=74%, P heterogeneity&lt;0.001) for all-cause mortality, 0.82 (0.79, 0.85; P &lt;0.001, I2=0%, P heterogeneity=0.53) for CVD mortality, and 0.88(0.83, 0.94; P &lt;0.001, I2=54%, P heterogeneity=0.02) for cancer mortality. Whole grain consumption was &lt;50 grams/day among most studies. Dose-response meta-analysis showed strong monotonic associations between whole grain and mortality (All P nonlinearity &gt; 0.05): RRs (95%CIs) for each 16 grams/day increase (approximately 1 serving/day) in whole grain were 0.93(0.92, 0.94) for all-cause mortality, 0.91(0.90, 0.93) for CVD mortality, and 0.95(0.94, 0.96) for cancer mortality. These findings were robust in several stratified analyses and/or sensitivity analyses. Egger’s test did not suggest significant publication bias. Conclusions: Our findings supported health benefit of increasing current whole grain intake of &lt;1 serving/day to ≥3 servings/day as recommended by current Dietary Guidelines for Americans.
Abstract 493: The landscape of adenosine signaling in cancer
Authors: Ben Sidders, Pei Zhang, Kelly Goodwin, Greg O'Connor, Alexandra Borodovsky, Jonathan Dry, Richard Woessner, Kris Sachsenmeier
Journal: Cancer Research (2019)

Abstract Adenosine is a key suppressor of immune cell function. CD73 and other nucleotidases/phosphatases dephosphorylate and convert extracellular AMP into adenosine, which binds the A2A adenosine receptor (A2aR). There are several agents in early clinical trials targeting components of the adenosine pathway including A2AR and CD73. The identification of cancers with a significant adenosine drive is therefore critical to our understanding of the potential for these molecules. However, it is challenging to measure tumour adenosine levels on a pan-cancer scale. Here we describe the generation &amp; validation of a gene expression signature that we use to characterise the pan-cancer landscape of adenosine signalling and its role within the tumour microenvironment. Natural Language Processing (NLP) was used to define a network of regulatory interactions between the A2aR receptor and downstream entities. 14 genes were identified as being positively regulated by A2aR and robustly expressed in tumours and so constitute the signature, which we demonstrate accurately recapitulates adenosine drive in mouse syngeneic models. We therefore applied the signature to a pan-cancer analysis of tumour transcriptomes from TCGA and found a significant negative impact on both overall survival (HR = 0.6, Cox PH p=0) and progression free survival (HR = 0.77, Cox PH p=0.0000006) in adenosine high tumours. An adenosine related survival deficit was also seen in CD8+ T-cell infiltrated tumours (OS HR = 0.47, Cox PH p=0; PFS HR = 0.65, Cox PH p=0.0000002). Studying adenosine signalling in the context of tumour genetics identified highly significant associations with TGFB super-family members including TGFBR2 (p=0.0000000013). These data support the adenosine pathway as a key mediator of a successful anti-tumour immune response, demonstrate the prognostic potential of the gene expression signature and could inform patient selection strategies for adenosine pathway modulators. Citation Format: Ben Sidders, Pei Zhang, Kelly Goodwin, Greg O'Connor, Alexandra Borodovsky, Jonathan Dry, Richard Woessner, Kris Sachsenmeier. The landscape of adenosine signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 493.
Analysis of Pathologic Complete Response 10 Weeks After Radiotherapy—A Radiobiological Sin
Authors: Juan C. Camacho, Etay Ziv, Stephen B. Solomon
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract 15456: In-vitro Assessment of Phrenic Nerve Cryothermal Injury
Authors: Ryan P Goff, Paul A Iaizzo
Journal: Circulation (2013)

Background: Phrenic nerve (PN) injury may result from transcatheter ablations for the treatment of arrhythmias. Cryoballoon ablation has been reported to cause phrenic nerve (PN) injury: occasional...
Abstract 147: Deletion of the RNA regulator HuR in microglia/macrophages promotes an anti-tumor microenvironment in glioblastoma
Authors: Jiping Wang, Jianmei Leavenworth, Anita Hjelmeland, Ben Borg, Peter H. King
Journal: Cancer Research (2019)

Abstract Glioblastoma is a malignant brain tumor that portends a poor prognosis. Its resilience, in part, is related to a remarkable capacity for manipulating the microenvironment to promote its growth and survival. Microglia/macrophages are a prime target, being drawn into the tumor and stimulated to produce factors that support tumor growth and immune system evasion. Here we show that the RNA regulator, HuR, plays a key role in the tumor-promoting response of microglia/macrophages. Knockout of HuR in microglia/macrophages led to reduced tumor growth and prolonged survival in a murine model of glioblastoma. Analysis of tumor composition by flow cytometry showed that tumor associated macrophages were decreased, more polarized toward an M1-like phenotype, and had attenuated PD-L1 expression. There was a concomitant reduction in tumor-associated polymorphonuclear myeloid-derived suppressor cells, but an increase in Treg cells. In vitro assays showed reduced migration of HuR-/- microglia toward secreted factors derived from glioblastoma cells, and a decrease in migration of glioblastoma cells toward secreted factors derived from HuR-/- microglia. The molecular response of HuR-/- microglia was altered including reduced CXCL1, 2, MMP2, PD-L1 and VEGF expression and an increase in CXCL10 and several MMPs. There was a mixed effect on cytokines and other factors associated with both proinflammatory and alternatively activated phenotypes. In summary, HuR is a key modulator of the tumor microenvironment in glioblastoma, promoting tumor progression through its molecular regulation of factors produced by microglia/macrophages. These findings underscore the relevance of HuR as a therapeutic target in glioblastoma. Citation Format: Jiping Wang, Jianmei Leavenworth, Anita Hjelmeland, Ben Borg, Peter H. King. Deletion of the RNA regulator HuR in microglia/macrophages promotes an anti-tumor microenvironment in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 147.
Abstract 1924: Rapid screening of anti-OX40 antibodies for cancer immunotherapy
Authors: Tian Gan, Yanan Li, Jian Ni, Benny(Yi) Yang
Journal: Cancer Research (2019)

Abstract OX40, also known as CD134 or TNFRSF4, is a member of the TNFR superfamily. OX40 is a co-stimulatory receptor, and it interacts with its ligand to provide positive signal for T cell activation. OX40 is not expressed on naïve T cells, however its expression goes up after 24 to 72 hours following activation. Disruption of the OX40 pathway led to defective T cell responses, and overexpression of OX40 caused massive immune activation. Due to its importance in keeping immune homeostasis, strategies modulating the OX40 pathway hold great promise in efforts against cancer and autoimmune diseases. Based on the promising nature of this target, we focused on developing novel OX40 agonists that would effectively stimulate anti-tumor activity. Dozens of high-affinity candidate antibodies were generated using classic hybridoma technology. In order to directly screen for antibodies for anti-tumor effects in animals, we ranked these antibodies in vivo using the drug screening platform based on humanized mouse models. Specifically, we used B-hOX40 mice and implanted syngeneic tumors subcutaneously, followed by treating mice with purified candidate antibodies. We quickly identified several lead antibodies that effectively inhibited tumor growth using this approach, without prior knowledge of their in vitro activities. Their ability to stimulate T cells was confirmed by an engineered reporter line of Jurkat T cells in vitro. Furthermore, we showed that one clone works in concert with Keytruda in a double humanized model of h-OX40 and h-PD-1. We are currently investigating the mechanisms of action underlying these potentially valuable antibodies and carrying out more combination evaluation studies using other available humanized immune-checkpoint mouse models. Citation Format: Tian Gan, Yanan Li, Jian Ni, Benny(Yi) Yang. Rapid screening of anti-OX40 antibodies for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1924.
Abstract 5212: Ablation of SMAD4 repression on <i>Elf3</i> promotes the progression of lung cancer <i>in vivo</i>
Authors: Jian Liu, Tianyuan Wang, San-pin Wu, Jian-liang Li, Francesco J. Demayo
Journal: Cancer Research (2019)

Abstract Lung cancer is the leading cause of cancer death among both men and women in United States. ELF3, a transcription factor, overexpresses in human and mouse lung cancer and plays an oncogenic role in lung cancer cells1,2. Understanding the regulatory mechanisms for ELF3 may help to develop related target therapies. Ablation of Smad4 and Pten in mice results in an increase of Elf3 expression and the development of adeno-squamous carcinoma1. Results from in vivo ChIP-Seq analysis demonstrate SMAD4 occupancy near the Elf3 promoter in the pulmonary epithelium1. Therefore, we hypothesize that this SMAD4 occupancy is required to repress Elf3 expression and subsequently suppresses lung cancer progression. To test this hypothesis, we deleted this SMAD4 binding region in vivo and characterized the phenotypic consequences. CRISPR/Cas9 was used to ablate the SMAD4 ChIP-Seq binding peak on Elf3 promoter region in mice. This resulted in mice with 12 and 17 nucleotide deletions in the Elf3 promoter region. ChIP-qPCR analysis showed that SMAD4 binding was decreased while H3K27ac bindings were increased in the Elf3 promoter region. The reduction in SMAD4 binding and the epigenetic changes in the Elf3 promoter region resulted in an increased expression of ELF3 in these lungs of these mice. Histological analysis of these mouse lungs showed the presence of pulmonary hyperplasia and the development of lung tumors. In order to identify potential interacting factors with SMAD4 in the Elf3 promoter, motif analysis of the deleted SMAD4 binding peak identified GATA2, ETS1 and OXT2 as potential interacting factors. In summary, small disruption of Elf3 promoter region bound by SMAD4 leads to the increase of ELF3 expression with the enhanced binding of H3K27ac and the decrease of SMAD4 binding and promotes lung hyperplasia and lung cancer development. SMAD4 may interact with GATA2, ETS2 and OXT2 in the regulation of Elf3expression. Key references 1. Liu, J. et al. ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis. Cell Rep, doi:10.1016/j.celrep.2015.02.014 (2015). 2. Wang, H. et al. Overexpression of ELF3 facilitates cell growth and metastasis through PI3K/Akt and ERK signaling pathways in non-small cell lung cancer. Int J Biochem Cell Biol 94, 98-106, doi:10.1016/j.biocel.2017.12.002 (2018). Note: This abstract was not presented at the meeting. Citation Format: Jian Liu, Tianyuan Wang, San-pin Wu, Jian-liang Li, Francesco J. Demayo. Ablation of SMAD4 repression on Elf3 promotes the progression of lung cancer in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5212.
Time-Varying Exposure to Air Pollution and Outcomes of <i>in Vitro</i> Fertilization among Couples from a Fertility Clinic
Authors: Audrey J. Gaskins, Kelvin C. Fong, Yara Abu Awad, Qian Di, Lidia Mínguez-Alarcón, Jorge E. Chavarro, Jennifer B. Ford, Brent A. Coull, Joel Schwartz, Itai Kloog, Irene Souter, Russ Hauser, Francine Laden
Journal: Environmental Health Perspectives (2019)

Background: A few studies suggest that air pollution may decrease fertility, but prospective studies and examinations of windows of susceptibility remain unclear. Objective: We aimed to examine the association between time-varying exposure to nitrogen dioxide (NO2), ozone (O3), fine particulate matter &lt;2.5μm (PM2.5), and black carbon (BC) on in vitro fertilization (IVF) outcomes. Methods: We included 345 women (522 IVF cycles) for the NO2, O3, and PM2.5 analyses and 339 women (512 IVF cycles) for the BC analysis enrolled in a prospective cohort at a Boston fertility center (2004–2015). We used validated spatiotemporal models to estimate daily residential exposure to NO2, O3, PM2.5, and BC. Multivariable discrete time Cox proportional hazards models with four periods [ovarian stimulation (OS), oocyte retrieval to embryo transfer (ET), ET to implantation, implantation to live birth] estimated odds ratios (OR) and 95% confidence intervals (CI) of failing at IVF. Time-dependent interactions were used to identify vulnerable periods. Results: An interquartile range (IQR) increase in NO2, PM2.5, and BC throughout the IVF cycle was associated with an elevated odds of failing at IVF prior to live birth (OR=1.08, 95% CI: 0.95, 1.23 for NO2; OR=1.06, 95% CI: 0.88, 1.28 for PM2.5; and OR=1.16, 95% CI: 0.96, 1.41 for BC). This relationship significantly varied across the IVF cycle such that the association with higher exposure to air pollution during OS was strongest for early IVF failures. An IQR increase in NO2, PM2.5, and BC exposure during OS was associated with 1.42 (95% CI: 1.20, 1.69), 1.26 (95% CI: 0.96, 1.67), and 1.23 (95% CI: 0.96, 1.59) times the odds of failing prior to oocyte retrieval, and 1.32 (95% CI: 1.13, 1.54), 1.27 (95% CI: 0.98, 1.65), and 1.32 (95% CI: 1.10, 1.59) times the odds of failing prior to ET. Conclusion: Increased exposure to traffic-related pollutants was associated with higher odds of early IVF failure. https://doi.org/10.1289/EHP4601
Abstract 14091: Cathepsin K Deficiency Attenuates Starvation-Induced Cardiac Autophagy and Apoptosis
Authors: Yinan Hua, Gou-Ping Shi, Jun Ren, Sreejayan Nair
Journal: Circulation (2013)

Cathepsin K, a lysosomal cysteine protease, is up-regulated in the heart in response to pressure-overload and knockout of cathepsin K protects against cardiac dysfunction associated with obesity an...
Global gene expression analysis indicates that multiple pathways are affected during growth arrest of non-malignant human mammary epithelial cells in three dimensional cell cultures
Authors: Marcia V. Fournier, Katherine J. Martin, Kris Xhaja, Irene Bosch, Mina Bissell, Paul Yaswen
Journal: Cancer Research (2005)

5402  The growth arrest of non-malignant human mammary epithelial cells (HMEC) in Matrigel provides a three dimensional model system in which to study a normal cell process that is disrupted in cancer. To systematically probe the molecular changes that lead to growth arrest in this system, we have analyzed the expression profiles of 22,283 gene transcripts using Affymetrix HG-U133A microarrays. Microarray experiments were performed using RNA samples harvested from HMT3522 S1 cells at 3, 5, and 7 days post-seeding in Matrigel. Growth arrest in G0/G1 occurred between days 5 and 7. Transcripts exhibiting greater than 2-fold differences in 2 independent experiments were analyzed by 1-way ANOVA. By these criteria, 354 genes, including many involved in cell cycle transit, cytokinesis, and mitosis, were found to be down-regulated, and 105 genes, including many involved in epidermal differentiation, inflammatory processes, and negative regulation of cell proliferation, were found to be up-regulated. About 5% of the 459 identified genes would be expected to show such changes by chance alone. Interestingly, among the cell cycle regulatory genes examined, p21 transcripts showed no change, while p27 transcripts showed strong up-regulation. We used immunoblot analyses to validate and extend the results of the microarray analyses at the protein level. We initially confined these analyses to cell cycle regulators known to affect G1 checkpoints. Phosphorylation of several sites on Rb was found to gradually decrease between days 5 and 10 in the non-malignant cells, consistent with the growth suppressive role of the hypophosphorylated form. When normalized to total protein content, levels of cyclins E, A, and D1, as well as their binding partners - CDK2, 4, and 6, also decreased in the non-malignant cells during this period. Protein levels of the CDK inhibitors - p27 and p57, increased between days 5 and 10, while levels of p21 did not change. Additional analysis of the HMEC strain, 184, led to the identification of MAP2K1, TGF-beta, ATR, and SMARCA4, as key regulatory genes whose expression and/or function was altered in common in the two different HMEC specimens early in the time course. In current studies, we are determining which of the pathways identified are required for growth arrest in the three dimensional HMEC cultures.
The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies
Authors: Dennis G McGonagle, Iain B McInnes, Bruce W Kirkham, Jonathan Sherlock, Robert Moots
Journal: Annals of the Rheumatic Diseases (2019)

Although the pathogenic mechanisms underlying axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are not fully elucidated, several lines of evidence suggest that immune responses mediated by interleukin 17A (IL-17A) play a pivotal role in both diseases. This is best highlighted by the significant clinical efficacy shown with inhibitors of IL-17A in treating axSpA and PsA. Nevertheless, a number of knowledge gaps exist regarding the role of IL-17A in the pathophysiology of spondyloarthritis in man, including its cellular origin, its precise role in discrete disease processes such enthesitis, bone erosion, and bone formation, and the reasons for the discrepant responses to IL-17A inhibition observed in certain other spondyloarthritis manifestations. In this review, we focus on the latest data from studies investigating the role of IL-17A in ankylosing spondylitis (AS) and PsA that build on existing and emerging scientific knowledge in the field. Key remaining research questions are also highlighted to guide future research.