tbuckley/cabot-search huggingface dataset:
Abstract 501: Tyrosyl-DNA phosphodiesterase I cellular function dependent on its N-terminal residues
Authors: Selma M. Cuya, Robert C.A.M. Van Waardenburg
Journal: Cancer Research (2017)

Abstract Tyrosyl-DNA phosphodiesterase I (Tdp1) is a highly conserved eukaryotic DNA repair enzyme that catalyzes the resolution of 3’ and 5’ phospho-DNA adducts. Tdp1 has been implicated in the repair of DNA topoisomerase I (Top1)-DNA covalent complexes reversibly stabilized by FDA approved camptothecins (CPTs) derivatives topotecan and irinotecan. Tdp1 activity relies on two catalytic histidines that function as a nucleophile and an acid-base residue. A mutation of the acid-base His to Arg (H493R) in human Tdp1 is associated with the rare recessive ataxia SCAN1. We defined alternative substitution of either catalytic histidine that induce cytotoxicity, reduce catalytic activity and enhances the requisite Tdp1-DNA covalent adduct lifetime in the cell. The phenotypes of the catalytic mutants provide excellent tools to study Tdp1 cellular function. Biochemical studies revealed that Tdp1 catalysis in vitro is independent of the N-terminal domain. Among Tdp1 proteins, the N-terminal domain is poorly conserved in sequence and size (79aa for yeast and 148aa for human Tdp1). Conversely, the N-terminal domain regulates the in vitro activity of these Tdp1 mutants. Additionally, we investigated the role of the N-terminal domain for Tdp1 activity in the yeast and human cell models. Expression of N-terminal truncated proteins showed similar cellular distribution as the full-length proteins. However, these N-terminal truncated Tdp1 mutants did not display the toxicity that was observed with the full-length Tdp1 mutant proteins. Our data suggests that the N-terminal domain is required to resolve protein-DNA covalent complexes, such as Top1. Indeed, preliminary results suggest that this domain is also critical to process Top2-DNA covalent complexes, but only in the presences of etoposide. We are currently investigating other protein-DNA adducts that are resolved by Tdp1. These results suggests that the N-terminal domain is a critical determinate of Tdp1 cellular function. However, further studies are necessary to ensure that these constructs are properly distributed and retain their catalytic activity. Additionally, the N-terminal domain of human Tdp1 is post-translational modified, while our preliminary results suggest that this domain is important for protein-protein interaction and Tdp1 recruitment to its substrates. Understanding Tdp1 substrate and protein-interactions are important in the development of Tdp1 as therapeutic target. This work is in part supported by the ADDA, UAB Cancer Comprehensive Center (P30CA013148), ACS-IRG-60-001-53, DOD OCRP (W81XWH-15-1-0198). Citation Format: Selma M. Cuya, Robert C.A.M. Van Waardenburg. Tyrosyl-DNA phosphodiesterase I cellular function dependent on its N-terminal residues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 501. doi:10.1158/1538-7445.AM2017-501
Abstract 1021: Mutations in SWI/SNF chromatin remodeling complex sensitize tumors to OXPHOS inhibition
Authors: Yonathan Lissanu Deribe
Journal: Cancer Research (2017)

Abstract Recent large-scale cancer genomic studies have established a framework in which biological functions and genetic interactions of established and novel cancer genes can be explored. One of the major findings of these studies has been the discovery of frequent genetic alterations in chromatin and epigenetic regulators including inactivating mutations in components of the SWI/SNF chromatin remodeling complex. In lung adenocarcinoma in particular, a quarter of tumors have inactivating mutations in the SWI/SNF components Smarca4, ARID1A or the histone modifier SETD2. With the aim of understanding the mechanism of tumor development and identifying potential vulnerabilities of SWI/SNF mutant tumor, we developed a genetically engineered mouse model (GEMM) of lung adenocarcinoma by selectively ablating Smarca4 in the respiratory epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss. Cross species integrative gene expression analyses revealed signatures of enhanced oxidative phosphorylation and reactive oxygen species (ROS) response in Smarca4 mutant murine and human lung tumors. We further show that Smarca4 mutant cells have increased oxygen consumption, enhanced basal and maximal respiratory capacity and production of ROS. This is primarily driven by activation of the mitochondrial master regulator, PGC1alpha. Finally, we show that Smarca4 and other SWI/SNF mutant lung cancer cell lines have exquisite sensitivity to inhibition of oxidative phosphorylation using a novel small molecule that is under development. These findings provide a mechanistic basis for further development of OXPHOS inhibitors as therapies in SWI/SNF mutant tumors. Citation Format: Yonathan Lissanu Deribe. Mutations in SWI/SNF chromatin remodeling complex sensitize tumors to OXPHOS inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1021. doi:10.1158/1538-7445.AM2017-1021
Abstract 1283: Mutations in theDuffy Antigen Receptor for Chemokines (DARC/ACKR1)gene result in population-private variants
Authors: Rachel Martini, Brittany Jenkins, Melissa Davis
Journal: Cancer Research (2017)

Abstract By studying the breast cancer microenvironment, we can specifically address novel aspects of cancer development and progression at the molecular level. Chemokines are small signaling molecules that are an important component of this microenvironment, as they shape cellular composition of this space through recruitment of immune cells, among other functions. DARC, the Duffy Antigen Receptor for Chemokines, is an atypical chemokine receptor (ACKR1) that can bind different classes of chemokines. It is a non-signaling receptor that mainly acts as a regulator of chemokine homeostasis by removing them from circulation to recruit appropriate immune cell types. The purpose of this study is to determine how population-private variants of the DARC/ACKR1 gene across global population render distinct function and define aspects of human diversity in immune responses. A well-studied example of this would be the Duffy-null allele. This allele carries a mutation that is population-specific to recent decedents of Sub-Saharan Africans, and removes expression of DARC on red blood cells. Loss of expression on red blood cells presumably causes these “Duffy-Null” individuals to lose the ability to sequester chemokines, therefore losing homeostatic balance of these molecules in circulation. To identify additional mutations, we completed in silico analysis of minor allele frequencies across the gene in the 1000 Genomes Project data, and identified several other putative functional mutations that likely result in additional gene variants, specific to geographic ancestry groups and likely under similar selection as the Duffy null allele. We have prioritized our initial functional study to include mutations in the regulatory regions of the gene, as these mutations can change how and where the gene is expressed. Future work is focused on investigating these functional variants in situ, using human tissue and human breast cell lines, by isolating and re-engineering ancestry-specific variants in these cell lines. By identifying and determining functional outcomes of these population-specific mutation, we can observe differences in immune responses across these global populations, further defining the role that DARC/ACKR1 plays in the breast tumor microenvironment. Citation Format: Rachel Martini, Brittany Jenkins, Melissa Davis. Mutations in the Duffy Antigen Receptor for Chemokines (DARC/ACKR1) gene result in population-private variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1283. doi:10.1158/1538-7445.AM2017-1283
La fibrose sous-muqueuse est une cause rare d’échec de POEM réalisé pour achalasia
Journal: Endoscopy (2017)

La myotomie perorale endoscopique est devenue une alternative à la myotomie de Heller avec un taux élevé de réussite technique et clinique. Toutefois, peu de données sont disponibles dans la littérature sur les causes et les conséquences de ces échecs techniques.
Abstract 81: E2F4/p107 complex regulates chemotherapy resistance in human colorectal cancer stem cells
Authors: Junichi Matsubara, Yong F. Li, Piero Dalerba, Debashis Sahoo, Taichi Isobe, Russ B. Altman, Michael F. Clarke
Journal: Cancer Research (2017)

Abstract Most cancer patients experience disease progression despite one or multiple lines of treatment with cytotoxic chemotherapy. Evidence from human trials and in vivo experiments on patient-derived xenograft (PDX) tumor lines indicates that cancer stem cells (CSCs) can survive chemotherapy treatment. However, the mechanism of chemotherapy resistance in CSCs is not fully elucidated. To identify new mechanisms of the drug-resistance in colorectal cancer, we used gene-expression microarrays to examine the gene expression profile of CSCs and non-CSCs in four human PDX models of colorectal cancer, both before-and-after treatment with cytotoxic chemotherapy. The gene-expression data were analyzed using Independent Component Analysis (ICA) followed by Transcription Factor Target Genes (TFTG) enrichment analysis, which identified the transcription factor E2F4 as a candidate regulator of chemotherapy resistance in colorectal CSCs. E2F4 was predominantly expressed in the CSC-enriched cell population (CD44+/CD166+ human colorectal cancer cells). E2F4 knock-down sensitizes cancer cells to chemotherapy in three different PDX tumors as well as HT29 cells. Co-immunoprecipitation experiments showed that E2F4 forms a complex with p107 and DP-1, which also contributed to the chemotherapy resistance. Simultaneous knock-down of both E2F4 and p107 enhanced chemotherapy sensitivity more than E2F4 knock-down alone. In normal intestinal crypt cells E2F4 was dispensable for chemotherapy resistance. ChIP-seq and RNA-seq experiments revealed that LDHA is a key downstream target of E2F4. LDHA knock-down sensitizes cancer cells to chemotherapy. High LDHA expression in tumor tissues was an independent poor prognostic factor in colorectal cancer patients (n=466), as well as in non-small cell lung cancer (n=1,926) and breast cancer (n=3,554). Thus, the E2F4/p107-LDHA pathway represents a novel therapeutic target to overcome chemotherapy resistance in CSCs. Citation Format: Junichi Matsubara, Yong F. Li, Piero Dalerba, Debashis Sahoo, Taichi Isobe, Russ B. Altman, Michael F. Clarke. E2F4/p107 complex regulates chemotherapy resistance in human colorectal cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 81. doi:10.1158/1538-7445.AM2017-81
Abstract 5939: Dissemination of breast cancer
Authors: Samata Kakkad, Mikayla Hanna, Desmond Jacob, Balaji Krishnamachary, Zaver M. Bhujwalla
Journal: Cancer Research (2017)

Abstract Breast cancer is the second leading cause of death in US women. Despite advances in early detection, diagnosis and treatment of breast cancer, metastasis and tumor recurrence persist leading to continued morbidity and mortality. Several breast cancer studies have highlighted the role of cyclooxygenase-2 (COX-2) and its interaction with the tumor microenvironment (TME) in breast cancer progression. The TME consists of stromal cells that include fibroblasts, macrophages, the extracellular matrix (ECM), and several secreted factors that contribute to aggressiveness of the cancer and resistance to therapy. Increased density of collagen 1 (Col1) fibers, a major structural component of the ECM in solid tumors, and their alignment in tumors frequently result in increased invasion and metastasis of cancer cells. To understand the role of COX-2 at the lung metastatic site, and its relationship with Col1 fibers, COX-2 overexpressing triple negative SUM-149 human breast cancer cells (SUM-149-COX-2) or empty vector SUM-149 cells (EV) were injected through tail vein in SCID mice to compare Col1 fiber patterns in metastatic lesions. We isolated the lungs, processed the tissue, and imaged for Col1 fiber by second harmonic generation microscopy on H&amp;E stained sections. The number of cancer associated fibroblasts (CAFs) were detected in adjacent sections by immunostaining for α-SMA. COX-2 overexpression did not increase the size of the cancer cell emboli in blood vessels or the size of pulmonary metastasis formed in the lungs. However, COX-2 overexpression did significantly increase the number of pulmonary metastases. Significantly higher Col1 fiber volume was observed in emboli compared to pulmonary metastases independent of COX-2 overexpression. Interestingly, the Col1 fibers were significantly more aligned in the COX-2 overexpressing pulmonary metastases compared to COX-2 overexpressing and EV emboli. The COX-2 overexpressing emboli had significantly higher amounts of CAFs detected by α-SMA expression compared to the EV emboli and the EV and COX-2 overexpressing pulmonary metastases. Pulmonary metastases from COX-2 overexpressing cells were detected further away from the nearest blood vessel compared to the metastases from EV cells suggesting that COX-2 may facilitate the formation of distant metastases. These data provide new insights into the role of COX-2, Col1 fibers, and CAFs in enabling emboli to extravasate to form pulmonary metastatic foci. These insights are important as COX-2 upregulation during treatment may potentiate metastasis. This work was supported by NIH R01 CA82337. Citation Format: Samata Kakkad, Mikayla Hanna, Desmond Jacob, Balaji Krishnamachary, Zaver M. Bhujwalla. Dissemination of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5939. doi:10.1158/1538-7445.AM2017-5939
Abstract 1147: Probing the roles of SUMOylation in cancer cell biology using a selective SUMO activating enzyme inhibitor
Authors: Sai M Pulukuri, Xingyue He, Stephen Grossman, Jessica Riceberg, Erik Koenig, Teresa Soucy, Keli Song, Anna Kreshock, Dylan England, Hirotake Mizutani, Larry Dick, James Brownell, John Newcomb, Steve Langston, Eric Lightcap, Katherine Galvin
Journal: Cancer Research (2017)

Abstract SUMOylation has been implicated in many cellular processes that are important for cancer cell survival, including cell cycle, chromosome structure and segregation, nuclear and subnuclear organization, transcription and DNA damage repair. However, a potent and selective inhibitor to target the SUMO pathway has been lacking. The SUMO-activating enzyme (SAE) is an essential enzyme in the pathway that initiates the SUMOylation process. Here we report the identification of the first mechanism-based SAE inhibitors with nanomolar potency in cellular assays. These inhibitors selectively block SAE enzyme activity and total SUMOylation in cells, which leads to reduced cancer cell proliferation. Moreover, SAE inhibition resulted in disruption of PML nuclear bodies and redistribution of DAXX. In vivo administration of SAE inhibitor into tumor bearing mice results in modulation of several biomarkers including a significant reduction in SUMO-conjugates and E2 Ubc9 thioesters, demonstrating SUMO pathway inhibition. Our results demonstrate the feasibility of inhibiting the SUMO pathway with small molecule inhibitors and provide tools to study the SUMO biology in cancer. Citation Format: Sai M Pulukuri, Xingyue He, Stephen Grossman, Jessica Riceberg, Erik Koenig, Teresa Soucy, Keli Song, Anna Kreshock, Dylan England, Hirotake Mizutani, Larry Dick, James Brownell, John Newcomb, Steve Langston, Eric Lightcap, Katherine Galvin. Probing the roles of SUMOylation in cancer cell biology using a selective SUMO activating enzyme inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1147. doi:10.1158/1538-7445.AM2017-1147
Risk of neonatal drug withdrawal after intrauterine co-exposure to opioids and psychotropic medications: cohort study
Authors: Krista F Huybrechts, Brian T Bateman, Rishi J Desai, Sonia Hernandez-Diaz, Kathryn Rough, Helen Mogun, Leslie S Kerzner, Jonathan M Davis, Megan Stover, Devan Bartels, Jennifer Cottral, Elisabetta Patorno
Journal: BMJ (2017)

<b>Objectives</b>&nbsp;To assess the impact of in utero co-exposure to psychotropic medications and opioids on the incidence and severity of neonatal drug withdrawal. <b>Design</b>&nbsp;Observational cohort study. <b>Setting</b>&nbsp;Nationwide sample of pregnancies in publicly insured women in the US, nested in the Medicaid Analytic eXtract (2000-10). <b>Participants</b>&nbsp;201 275 pregnant women with public insurance who were exposed to opioids around the time of delivery and their liveborn infants. <b>Interventions</b>&nbsp;In utero exposure to psychotropic medications, in particular antidepressants, atypical antipsychotics, benzodiazepines, gabapentin, and non-benzodiazepine hypnotics (Z drugs), with prescriptions filled within the same time window as prescriptions for opioids. <b>Main outcome measure</b>&nbsp;Diagnosis of neonatal drug withdrawal in infants exposed in utero to opioids and psychotropic medications compared with opioids alone. <b>Results</b>&nbsp;The absolute risk for neonatal drug withdrawal ranged from 1.0% in infants exposed in utero to prescription opioids alone to 11.4% for those exposed to opioids co-prescribed with gabapentin. Among neonates exposed in utero to prescription opioids, the relative risk adjusted for propensity score was 1.34 (95% confidence interval 1.22 to 1.47) with concomitant exposure to antidepressants, 1.49 (1.35 to 1.63) with benzodiazepines, 1.61 (1.26 to 2.06) with gabapentin, 1.20 (0.95 to 1.51) with antipsychotics, and 1.01 (0.88 to 1.15) with Z drugs. In utero exposure to two or more psychotropic medications along with opioids was associated with a twofold increased risk of withdrawal (2.05, 1.77 to 2.37). The severity of the withdrawal seemed increased in neonates exposed to both opioids and psychotropic medications compared with opioids alone. <b>Conclusions</b>&nbsp;During pregnancy, the use of psychotropic medications in addition to prescription opioids is common, despite a lack of safety data. The current findings suggest that these drugs could further increase the risk and severity of neonatal drug withdrawal.
Abstract 5916: Proton-sensor GPR4 potentiates intestinal inflammation in the DSS-induced colitis mouse model
Authors: Edward J. Sanderlin, Nancy R. Leffler, Kvin Lertpiriyapong, Qi Cai, Heng Hong, Vasudevan Bakthavatchalu, James G. Fox, Joani Z. Oswald, Calvin R. Justus, Elizabeth A. Krewson, Dorcas O’Rourke, Li V. Yang
Journal: Cancer Research (2017)

Abstract Inflammation and tissue acidosis are two factors that co-exist in inflammatory bowel disease (IBD) and can contribute to increased risk of colorectal cancer (CRC) development. GPR4 is a proton-sensing G protein-coupled receptor that can be activated by extracellular acidosis through several histidine residues and subsequently signal through downstream G-protein pathways. Recently, GPR4 has been shown to be activated by acidosis and can increase the expression of numerous inflammatory and stress response genes in vascular endothelial cells (ECs) and has functionally increased EC-leukocyte adhesion. Subsequently, genetic and small molecule approaches for the inhibition of GPR4 activity have reduced endothelial cell inflammation. In this study, we examined the role of GPR4 in intestinal inflammation using a dextran sulfate sodium (DSS)-induced colitis mouse model. We observed that GPR4 mRNA expression was increased in mouse and human IBD tissues when compared to control intestinal tissues. To determine the function of GPR4 in intestinal inflammation, wild-type and GPR4-deficient mice were treated with 3% DSS for acute and chronic time points for the induction of colitis. Our results showed that the severity of colitis was decreased in GPR4-deficient DSS-treated mice in comparison to wild-type DSS-treated mice. Clinical parameters, macroscopic disease indicators, and histopathological features were less severe in the DSS-treated GPR4-deficient mice than the DSS-treated wild-type mice. Inflammatory gene expression, endothelial adhesion molecule expression, leukocyte infiltration, and isolated lymphoid follicle (ILF) formation were reduced in intestinal tissues of DSS-treated GPR4-null mice. In summary, our results suggest GPR4 potentiates intestinal inflammation as the absence of GPR4 ameliorates intestinal inflammation in the DSS-induced colitis mouse model. Use of GPR4 inhibitors could prove a valuable therapeutic in the reduction of intestinal inflammation and subsequent CRC development. Note: This abstract was not presented at the meeting. Citation Format: Edward J. Sanderlin, Nancy R. Leffler, Kvin Lertpiriyapong, Qi Cai, Heng Hong, Vasudevan Bakthavatchalu, James G. Fox, Joani Z. Oswald, Calvin R. Justus, Elizabeth A. Krewson, Dorcas O’Rourke, Li V. Yang. Proton-sensor GPR4 potentiates intestinal inflammation in the DSS-induced colitis mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5916. doi:10.1158/1538-7445.AM2017-5916
The number sense is neither last resort nor of primary import
Authors: Michael J. Beran, Audrey E. Parrish
Journal: Behavioral and Brain Sciences (2017)

Abstract Leibovich et al. argue that evidence for an innate sense of number in children and animals may instead reflect the processing of continuous magnitude properties. However, some comparative research highlights responding on the basis of numerosity when non-numerical confounds are controlled. Future comparative tests might evaluate how early experience with continuous magnitudes affects the development of a sense of number.