tbuckley/cabot-search huggingface dataset:
Abstract 1094: Lipopolysaccharide-induced chronic inflammation promotes lung tumorigenesis in the context of an immunosuppressive microenvironment
Authors: Chia-Hsin Liu, Kong Chen, Yuanpu Di
Journal: Cancer Research (2019)

Abstract Clinical and epidemiological evidence suggest that chronic infection and inflammation increase risk of lung cancer. Pseudomonas aeruginosa infection is frequently found in patients with chronic obstructive pulmonary disease (COPD) and is associated with increased lung inflammation and acute exacerbations. However, the mechanism of chronic bacterial infection-induced lung inflammation in promoting lung tumorigenesis remains unclear. To elucidate this mechanism, we established a murine lung cancer model by treating mice with or without recurrent lipopolysaccharides (LPS) from Pseudomonas aeruginosa in combination with nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Interestingly, combined LPS and NNK exposure significantly increased tumor number, tumor incidence, and tumor area compared to NNK treatment alone. In addition, the inflammatory cell counts in the bronchoalveolar lavage (BAL) including macrophages, neutrophils, and lymphocytes were significantly increased in the LPS/NNK treatment group. The BAL fluid of chemokines/cytokines, as analyzed by luminex assays, revealed higher levels of IL-17, CXCL10, GM-CSF, G-CSF, MIP-1a, and KC in LPS/NNK than in NNK treatment group. Flow cytometry analysis of the mouse lung tissue revealed that combined LPS and NNK exposure significantly increased CD4+ T cells including Th1, Th17, and Tregs and myeloid-derived suppressor cells recruitment in the lung. Real-time polymerase chain reaction of mouse lung tissue showed T cell exhaustion related genes, including Pdcd1, Ctla-4, Tim-3, Lag-3, and Foxp3, were significantly upregulated in the LPS/NNK treatment than NNK treatment. Moreover, immunohistochemical staining of LPS/NNK-exposed lung tumors showed higher PD-L1 expression than NNK-exposed lung tumors. Our data suggest that chronic LPS exposure-promoted and NNK-induced lung tumorigenesis is associated with immunosuppressive tumor microenvironment. The changes include recruitment of Tregs and MDSCs, increased T cell exhaustion, and upregulated PD-1/PD-L1 pathway, which may be used as the therapeutic target for chronic inflammation-associated lung cancer treatment. Citation Format: Chia-Hsin Liu, Kong Chen, Yuanpu Di. Lipopolysaccharide-induced chronic inflammation promotes lung tumorigenesis in the context of an immunosuppressive microenvironment [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 1094.
Detecting the disappearance of RAS-mutant clones in the plasma of patients with RAS-mutant mCRC to select patient candidates for anti-EGFR treatment and to monitor resistance to treatment
Authors: C. Raimondi, F. Loreni, C. Nicolazzo, F. Belardinilli, A. Wilson, A. Gradilone, G. Giannini, P. Gazzaniga, E. Cortesi
Journal: Annals of Oncology (2019)
Abstract 373: Dysregulated RPB1 is a key driver of overgrowth and drug resistance in acute myeloid leukemia
Authors: Qingfeng Yu, Shu Zheng, Ying Xu, Rongzhen Xu
Journal: Cancer Research (2019)

Abstract Acute myeloid leukemia (AML) is a group of highly aggressive malignancies with a 5-year overall survival (OS) of &amp;lt;40%. Cell overgrowth with apoptosis resistance is a hallmark of AML, but little is known about how it occurs. In this study, we show that dysregulated the largest subunit of RNA polymerase II (RPB1) encoded by POLR2A gene is critically involved in this hallmark in AML. qRT-PCR and RNA-seq results showed that POLR2A mRNA were significantly overexpressed in 76.87% (113/147) compared with normal hematopoietic cells(1.5526 versus 0.8447, P&amp;lt;0.001). Western blotting analysis revealed that RPB1 protein is also aberrantly activated in 68.14%(67/113) of AML patients but rare or even absent in normal hematopoietic cells, (0.7889 versus 0.0509, P&amp;lt;0.01). TCGA data analysis indicated that aberrant activation of POLR2A mRNA occurred predominantly in AML, CHOL and THYM, but not in most other types of cancers. Importantly, we observed that RPB1 expression levels were closely associated with tumor burden and poor prognosis. Notably, we found that POLR2A inhibition induced potent apoptosis and growth inhibition of refractory AML cells. Global transcriptomic analysis reveals that POLR2A knockout selectively depleted an array of AML-related oncogenic and anti-apoptosis genes such as c-MYC, RUNX2, MEIS1, FLT3, CDC25A and BCL-2. Conversely, enforced overexpression of RPB1 exhibits robust enrichment of oncogenes and anti-apoptosis genes, leading to cell overgrowth and drug resistance. Of particular interesting, targeting RPB1 by both genetic and pharmacological molecules could lead complete regression of refractory human AML in mouse models. In conclusion, our findings for the first time reveal that dysregulated RPB1 is a central oncogenic hub that drives overgrowth and drug resistance by coordinately hijacking an array of oncogenic genes and anti-apoptosis factors. Importantly, RPB1 is not absolutely required for the survival of normal hematopoietic cells, which is contrary to the commonly accepted belief that RPB1, the heart of the cellular transcription machinery, is required for all protein-coding genes. These data suggest that targeting RPB1 might be a potential therapeutics for treating refractory/relapse AML. Note: This abstract was not presented at the meeting. Citation Format: Qingfeng Yu, Shu Zheng, Ying Xu, Rongzhen Xu. Dysregulated RPB1 is a key driver of overgrowth and drug resistance in acute myeloid leukemia [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 373.
Assessment of Strategies for Managing Expansion of Diagnosis Coding Using Risk-Adjustment Methods for Medicare Data
Authors: Yusuke Tsugawa, Jose F. Figueroa, Irene Papanicolas, E. John Orav, Ashish K. Jha
Journal: JAMA Internal Medicine (2019)

This study of 100% Medicare Inpatient Files assesses strategies for managing coding of comorbidities associated with hospitalization before and after Centers for Medicare & Medicaid coding changes.
Abstract 3896: Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (<i>nab</i>-Sirolimus)
Authors: Shihe Hou, Anita Schmid, Neil Desai
Journal: Cancer Research (2019)

Abstract Background: Activation of the mTOR signaling pathway is frequently observed in multiple types of cancer. The poor solubility and low oral bioavailability of the mTOR inhibitor sirolimus limit its development as an anticancer therapy. ABI-009 (nab-sirolimus) is an injectable nanoparticle form of human albumin-bound sirolimus developed with a proprietary nanoparticle albumin-bound (nab®) technology. Currently, numerous phase 1 and 2 clinical studies are ongoing with ABI-009, including a registrational phase 2 study for the treatment of malignant perivascular epithelioid cell carcinoma (PEComa), and various oncology (bladder cancer, soft-tissue sarcomas, neuroendocrine tumors, colorectal cancer, glioblastoma, and various childhood cancers) as well as in non-oncology indications (pulmonary arterial hypertension (PAH), pediatric epilepsy, and mitochondrial diseases). Several nonclinical studies were conducted to evaluate pharmacokinetics, tissue distribution and in particular, CNS penetration of ABI-009. Methods: Rats were intravenously (IV) administered with a single dose of ABI-009 at 1.7, 9.5, and 17 mg/kg. Blood and organs were collected at 2, 8, 24, 72, and 120 hrs to analyze for sirolimus concentrations. Results: There is a generally linear dose response with sirolimus concentrations in blood, heart, lung, liver, and pancreas following a single dose of IV ABI-009. Sirolimus concentrations in blood and well-perfused organs had high peaks at earlier time points but dropped quickly with time, with the highest concentrations observed in lung. In contrast, sirolimus concentrations in brain rose slowly at first, but maintained at a steady level over time. After 5 days, sirolimus level in the brain was similar to other organs, suggesting substantial and prolonged drug distribution to the brain with ABI-009. Organ/blood ratios of most organs increased with time, with the brain/blood ratios increasing more significantly over time. Higher initial dose of ABI-009 resulted in increased brain/blood ratios. Conclusions: ABI-009 administered IV demonstrated a distinct PK profile compared with oral mTOR inhibitors. The PK of ABI-009 is characterized by higher Cmax and AUC, and rapid tissue distribution. Combined with efficient tumor penetration observed in a xenograft study, results of this study support the potential use of ABI-009 for the treatment of cancers in different organ sites, including lung, brain, liver, and pancreas. These findings also warrant further clinical studies in non-oncology indications including PAH and disorders involving the CNS. Citation Format: Shihe Hou, Anita Schmid, Neil Desai. Distinct pharmacokinetics, tissue distribution and CNS penetration of ABI-009 (nab-Sirolimus) [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 3896.
Abstract 2233: Correlation between mutations found in FFPE tumor tissue and paired cfDNA samples
Authors: Lauren Saunders, Antonia Hur, Brittany Niccum, Asmita Patel
Journal: Cancer Research (2019)

Abstract Cell free DNA (cfDNA) consists of small (150 - 500 bp) DNA fragments that circulate in the blood. cfDNA levels tend to be low in healthy, non-pregnant patients, and increase in patients with cancer, pregnancy, or extensive damage to tissue. cfDNA is believe to derive mostly from apoptotic cells, and biomarkers for a variety of diseases have been found in cfDNA. As cfDNA is extracted from blood, it is a non-invasive way to detect disease; however, there is some concern that cfDNA does not contain the same biomarkers as tumor tissue. This study measures the efficacy of cfDNA as a biomarker detection medium by comparing mutations found in both FFPE tumor samples and paired cfDNA samples. This study determines whether the same biomarkers are found in each sample type, and which of those can be used as biomarkers in both and which are preferred biomarkers for only a single sample type. Trends in mutation detection with the two different sample types are discussed. Citation Format: Lauren Saunders, Antonia Hur, Brittany Niccum, Asmita Patel. Correlation between mutations found in FFPE tumor tissue and paired cfDNA samples [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 2233.
Maternal and Child Health After Prenatal Opioid Exposure
Authors: Susan Brogly
Journal: JAMA Network Open (2019)

Romuladus E. Azuine, DrPH, MPH, RN; Yuelong Ji, PhD; Hsing-Yuan Chang, MD, MPH; Yoona Kim, MPH; Hongkai Ji, PhD; Jessica DiBari, PhD; Xiumei Hong, MD, PhD; Guoying Wang, MD, PhD; Gopal K. Singh, PhD; Colleen Pearson, BA; Barry Zuckerman, MD; Pamela J. Surkan, ScD; Xiaobin Wang, MD, MPH, ScD
Comparison of Proteasome Inhibitors-Induced Cardiotoxicity (carfilzomib vs. bortezomib): Insights into the Molecular Mechanisms
Authors: Georgios Kremastiotis, Panagiotis Efentakis, Aimilia Varela, Constantinos H. Davos, Eleni-Dimitra Papanagnou, Ioannis P. Trougakos, Eftathios Kastritis, Evangelia Chavdoula, Efstathios Iliodromitis, Apostolos Klinakis, Meletios A. Dimopoulos, Ioanna Andreadou, Evangelos Terpos
Journal: Blood (2017)
Abstract 4411: Identification of novel natural compounds as potential inhibitors of cyclin dependent kinases
Authors: Ranjini Sankaranarayanan, Rakesh Dachineni, Siddharth Kesharwani, Ramesh Kumar Dhandapani, Hemachand Tummala, Jayarama B. Gunaje
Journal: Cancer Research (2019)

Abstract Colorectal cancer (CRC) is the second highest cause of cancer deaths in the United States according to CDC (2017). Lifestyle factors including, but not limited to, elevated Body Mass Index (BMI), obesity and diet are proposed to lead to the development of CRC with an estimated annual incidence of 95,520 cases. Increasing evidences suggest that a diet rich in fruits and vegetables will reduce incidences of colorectal adenomas. We hypothesize that the natural compounds present in fruits and vegetables, along with their metabolites generated by the gut microbiota, could be responsible for cancer prevention by targeting the cell cycle proteins. In this study, we investigated the ability of polyphenols [Epigallocatechin Gallate (EGCG), Catechin, Catechin Gallate (CG), and Epigallocatechin (EGC)] and their degradation products [Phloroglucinol; 2,4,6 Trihydroxybenzoic acid (2,4,6 THBA); 3,4 Dihydroxyhydrocinnamic acid (3,4-DHHCA); etc.] to inhibit the CDKs (that regulate cell cycle) activity. Our pilot studies show that the different catechin compounds and their degradation products are capable of inhibiting different CDKs, suggesting their potential role in cancer prevention. We are currently investigating the mechanism of inhibition of CDKs by these compounds utilizing biochemical and molecular docking studies. Elucidation of this pathway will suggest the role of polyphenols in the prevention of CRC as well as assist in the identification of novel compounds that can be used for both cancer prevention and therapy. Citation Format: Ranjini Sankaranarayanan, Rakesh Dachineni, Siddharth Kesharwani, Ramesh Kumar Dhandapani, Hemachand Tummala, Jayarama B. Gunaje. Identification of novel natural compounds as potential inhibitors of cyclin dependent kinases [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 4411.
Abstract 17478: Cost Effectiveness of Left Atrial Appendage Closure in Atrial Fibrillation Patients With Previous Stroke or Transient Ischemic Attack
Authors: Vivek Y Reddy, Ronald L Akehurst, Stacey L Amorosi, Shannon Armstrong, David R Holmes
Journal: Circulation (2013)

Purpose: Once a patient with atrial fibrillation (AF) experiences an embolic event the probability of a second event increases 2.6 fold. The WATCHMAN device for left atrial appendage closure (LAAC)...
Abstract 1464: Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation
Authors: Yan Luo, Shreeder Barath, Deborah A. Bahr, Navnita Dutta, Geraldine Raja, Martin J. Cannon, Keith L. Knutson
Journal: Cancer Research (2019)

Abstract Dendritic cells (DCs) are the most potent antigen-presenting cells which bridges innate and adaptive immunity, but how DC-derived signals regulate and induce T cell lineage choices remains unclear. The p38 MAPK pathway plays an essential role in regulating cellular processes such as cell differentiation, growth, and death. In this study, SB203580 was employed to selectively inhibit p38 pathway in bone marrow derived DCs (BMDCs) to investigate the effects of this pathway on the characteristic phenotype and function of DCs, especially the induction on T helper cell differentiation. We found that inhibition of p38 increased the proliferation of BMDCs, but did not alter their phagocytic ability. Also, inhibition of p38 enhanced the activation of BMDCs, as evidenced by the up-regulated expression of DCs-related surface markers including CD80, CD86 and MHCII. However, the secretion levels of IL-12 and IL-10 in BMDCs were reduced significantly, whereas the level of IL-6 was not influenced by the p38 inhibitor. In addition, we immunized the mice with BMDCs vaccines and studied the production of antigen-specific Th17 T cell in spleen. Our data demonstrated that p38-inhibited DCs vaccine could induce more antigen-specific Th17 T cells than regular DCs vaccine in vivo. Collectively, these results support the hypothesis that the p38 pathway plays a critical role in the immunologic activation of DCs. Our findings suggest that inhibition p38 pathway in DCs may be a new strategy for generating potent DC vaccines for cancer immunotherapy. Citation Format: Yan Luo, Shreeder Barath, Deborah A. Bahr, Navnita Dutta, Geraldine Raja, Martin J. Cannon, Keith L. Knutson. Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation [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 1464.
Prognostic significance of chronic respiratory symptoms in individuals with normal spirometry
Authors: Yunus Çolak, Børge G. Nordestgaard, Jørgen Vestbo, Peter Lange, Shoaib Afzal
Journal: European Respiratory Journal (2019)

Normal spirometry is often used to preclude airway disease in individuals with unspecific respiratory symptoms. We tested the hypothesis that chronic respiratory symptoms are associated with respiratory hospitalisations and death in individuals with normal spirometry without known airway disease. We included 108 246 randomly chosen individuals aged 20–100 years from a Danish population-based cohort study. Normal spirometry was defined as a pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity ratio ≥0.70. Chronic respiratory symptoms included dyspnoea, chronic mucus hypersecretion, wheezing and cough. Individuals with known airway disease, i.e. chronic obstructive pulmonary disease and/or asthma, were excluded (n=10 291). We assessed risk of hospitalisations due to exacerbations of airway disease and pneumonia, and respiratory and all-cause mortality, from 2003 through 2018. 52 999 individuals had normal spirometry without chronic respiratory symptoms and 30 890 individuals had normal spirometry with chronic respiratory symptoms. During follow-up, we observed 1037 hospitalisations with exacerbation of airway disease, 5743 hospitalisations with pneumonia and 8750 deaths, of which 463 were due to respiratory disease. Compared with individuals with normal spirometry without chronic respiratory symptoms, multivariable adjusted hazard ratios for individuals with normal spirometry with chronic respiratory symptoms were 1.62 (95% CI 1.20–2.18) for exacerbation hospitalisations, 1.26 (95% CI 1.17–1.37) for pneumonia hospitalisations, 1.59 (95% CI 1.22–2.06) for respiratory mortality and 1.19 (95% CI 1.13–1.25) for all-cause mortality. There was a positive dose–response relationship between number of symptoms and risk of outcomes. Results were similar after 2 years of follow-up, for never-smokers alone, and for each symptom separately. Chronic respiratory symptoms are associated with respiratory hospitalisations and death in individuals with normal spirometry without known airway disease.
Abstract SY36-01: Decoding the biochemical, regulatory, and clinical impact of genomic mutations
Authors: Olga Troyanskaya
Journal: Cancer Research (2019)

Abstract A key challenge in precision medicine lies in decoding the complexity of the functional effects of genome variation to determine which mutations are functional and what are their biochemical and phenotypic consequences. This question is especially difficult for the 98% of the genome that is outside of exomes. To address this challenge we developed deep learning-based methods, DeepSEA and SeqWeaver, that predict the transcriptional and post-transcriptional effects of noncoding variants with single-nucleotide sensitivity. These methods not only classify mutations as likely to be associated with disease, they also provide specific biochemical consequences of each mutation, including on transcription factor and RBP binding, histone modification, and DNA accessibility. Building upon these findings, we created a deep learning-based framework, ExPecto, that can accurately predict, ab initio from DNA sequence alone, the tissue-specific transcriptional effects of mutations. These methods thus provide a platform for predicting and characterizing specific mutational impact for any genomic mutation, including those that are rare or that have not been observed. Applying these methods (available at hb.flatironinstitute.org) to whole genomes in a number of diseases, including cancer, autism, and heart disease, we demonstrate the contribution of de novo noncoding mutations and analyze the functional landscape of noncoding cancer-associated mutations. Citation Format: Olga Troyanskaya. Decoding the biochemical, regulatory, and clinical impact of genomic mutations [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 SY36-01.
Abstract 2093: Drug induced autophagy and transcriptional gene expression signatures in breast cancer cell lines
Authors: Francesca Mascia, Kostantinos Karagiannis, Wells W. Wu, Rong-Fong Shen, Ashutosh Rao
Journal: Cancer Research (2019)

Abstract Cancer cells can bypass the desired cell death response to chemotherapy through cytoprotective autophagy. In support of this hypothesis, drug resistant clones display higher basal autophagy than the correspondent drug sensitive cell lines. Autophagy therefore represents a potential target to reduce drug resistance and to enhance drug efficacy. We induced autophagy in several breast cancer cell lines with differing ER/PR/Her2 status by exposing them to tamoxifen (MCF-7/ER positive cells), trastuzumab (SKBR3/Her2 positive cells), bortezomib and rapamycin (MDA-MB-231 triple negative cells) in the presence and absence of an autophagy inhibitor such as hydroxychloroquine. While the ongoing autophagy flux process was confirmed by the amount of LC3II at the lipidated protein level, total RNA was extracted at the same time to perform RNA sequencing analysis. We performed differential expression analysis between all the drug treatments and the relative basal level of each cell type obtaining a cell and drug-specific gene list. We then compared all the gene lists to find a common, cell and drug-independent signature. Bioinformatic analysis was performed using the software IPA (Ingenuity Pathway Analysis) and setting a threshold of 0.01 for the p value. This analysis suggested a set of canonical pathways that are significantly and commonly affected in all the samples tested. The top canonical pathways disrupted in all the gene sets were the one identified as tRNA charging, CHK proteins in cell cycle check point control, hypoxia signaling and unfolded protein response. We plan to further identify the smallest gene list that is associated with the disruption of all these pathways across all the cells. This signature may help to uncover a consistent biomarker of autophagy that can be used during preclinical and clinical drug development aiming to reduce or eliminate drug resistance and improve cancer treatment outcomes. Citation Format: Francesca Mascia, Kostantinos Karagiannis, Wells W. Wu, Rong-Fong Shen, Ashutosh Rao. Drug induced autophagy and transcriptional gene expression signatures in breast cancer cell lines [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 2093.