tbuckley/cabot-search huggingface dataset:
Abstract 874: The CRTC1/MAML2 oncogene induces a PGC-1a splice variant that sensitizes mucoepidermoid carcinoma cells to PPARg inhibition
Authors: Adele M. Musicant, Kshitij P. Sharma, Erin C. Henry, Jason Tasoulas, Ricardo Padilla, Monideepa Sengupta, Colin Flaveny, Antonio L. Amelio
Journal: Cancer Research (2019)

Abstract Mucoepidermoid carcinoma (MEC) is the most common type of malignant salivary gland tumor. MECs frequently exhibit a recurrent t(11;19)(q21;p13) chromosomal translocation that fuses the transcriptional coactivators CRTC1 (CREB-Regulated Transcription Coactivator 1; C1) and MAML2 (Mastermind-Like 2; M2). Though many C1/M2-positive tumors are easily resected, some do progress to advanced, metastatic disease accompanied by poor 5-year survival rates. Thus, it is critical to understand the mechanisms by which C1/M2 drives tumor growth and progression in order to identify therapeutic vulnerabilities. Our lab recently identified a correlation between C1/M2 expression and increased levels of the growth hormone IGF-1. This hormone plays critical roles in the development and homeostasis of normal salivary glands, and its dysregulation has been implicated in several cancers including colon and lung cancers. Interestingly, we demonstrate that IGF-1 is not directly upregulated by C1/M2. Rather, we have discovered a novel C1/M2-driven signaling circuit whereby constitutive CREB activation drives the increased production of a minor PGC-1α (PPARγ Coactivator 1α) splice variant, PGC-1α4, which is responsible for the high IGF-1 levels observed in C1/M2-positive MEC cells. Notably, the PGC-1α4 splice variant is minimally expressed in normal tissues and C1/M2-negative cell lines but is selectively upregulated in C1/M2-positive cell lines. We show that C1/M2 directly binds CREB at the PGC-1α4 promoter to induce expression of this variant, resulting in increased IGF-1 expression. IGF-1 promoter analysis revealed a significant enrichment of PPARγ binding motifs and functional studies confirm that this promoter is regulated by PPARγ. Consequently, we demonstrate that a novel PPARγ inverse agonist is capable of repressing IGF-1 promoter activity and reducing growth and clonogenic potential of C1/M2-positive cell lines that exhibit high PGC-1α4 expression. Collectively, our results reveal a novel therapeutic vulnerability in salivary MEC cells that may extend more broadly to other cancers that exhibit dysregulated CREB activity. Citation Format: Adele M. Musicant, Kshitij P. Sharma, Erin C. Henry, Jason Tasoulas, Ricardo Padilla, Monideepa Sengupta, Colin Flaveny, Antonio L. Amelio. The CRTC1/MAML2 oncogene induces a PGC-1a splice variant that sensitizes mucoepidermoid carcinoma cells to PPARg inhibition [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 874.
Abstract 4801: 2’-Hydroxyflavanone, a diet-derived citrus bioflavonoid, inhibits <i>in vitro</i> and <i>in vivo</i> growth of breast cancer cells by targeting RLIP
Authors: Sharad S. Singhal, Shireen Chikara, Jyotsana Singhal, David Horne, Ravi Salgia, Sanjay Awasthi
Journal: Cancer Research (2019)

Abstract Breast cancer remains one of the major causes of cancer deaths in women. Consumption of citrus-fruits is associated with reduced incidence of breast cancer, the most common cancer diagnosed in women across the globe. In this study, we investigated the anticancer potential of 2-Hydroxyflavanone (2HF) in breast cancer. 2HF, a citrus-bioflavonoid, has demonstrated anticancer properties in various cancers, but its anticancer role in breast cancer has not been well studied. We investigated the in-vitro and in-vivo growth inhibitory effects of 2HF in an array of BC lines and in xenograft mouse models of ER-positive and HER2-positive breast cancer cells. Compared to control, 2HF treatment reduced cell viability of breast cancer cells, while, no growth inhibitory effects were observed in non-tumorigenic breast epithelial cells. Further, 2HF inhibited the expression of RLIP, a stress-defensive and anti-apoptotic protein, which is over-expressed in breast cancer cells and simultaneously reduced proliferation of breast cancer cells. Nude mice bearing MCF7 or SKBR3 breast cancer cells xenografts treated with either 2HF or targeting RLIP by RLIP-antisense or RLIP-antibody treatment had significantly lower tumor-weight as compared to corresponding controls. In addition, Western-blotting and immunohistochemical analysis of tumor tissue from control and treatment group mice showed that 2HF decreased protein expression levels of RLIP, and the decrease was similar to those seen following RLIP-antisense treatment. Furthermore, 2HF decreased expression of Ki67, CD31, vimentin, inhibited phosphorylation of AKT and expression of survivin and Bcl2, and increased levels of Bax, E-cadherin, and cleaved-PARP. Therefore, our results indicate that 2HF may suppress breast cancer growth in-vitro and in-vivo by targeting RLIP, and may serve as a potential adjuvant treatment in breast cancer patients. (This work was supported in part by the Department of Defense grant W81XWH-16-1-0641. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Shireen Chikara, Jyotsana Singhal, David Horne, Ravi Salgia, Sanjay Awasthi. 2’-Hydroxyflavanone, a diet-derived citrus bioflavonoid, inhibits in vitro and in vivo growth of breast cancer cells by targeting RLIP [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 4801.
Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis
Authors: Brett Ley, Dara G. Torgerson, Justin M. Oldham, Ayodeji Adegunsoye, Shuo Liu, Jie Li, Brett M. Elicker, Travis S. Henry, Jeffrey A. Golden, Kirk D. Jones, Amy Dressen, Brian L. Yaspan, Joseph R. Arron, Imre Noth, Thomas J. Hoffmann, Paul J. Wolters
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).
Comparison of<i> CDH1</i> Penetrance Estimates in Clinically Ascertained Families vs Families Ascertained for Multiple Gastric Cancers
Authors: Maegan E. Roberts, John Michael O. Ranola, Megan L. Marshall, Lisa R. Susswein, Sara Graceffo, Kelsey Bohnert, Ginger Tsai, Rachel T. Klein, Kathleen S. Hruska, Brian H. Shirts
Journal: JAMA Oncology (2019)

CDH1 pathogenic variants have been estimated to confer a 40% to 70% and 56% to 83% lifetime risk for gastric cancer in men and women, respectively. These are likely to be overestimates owing to ascertainment of families with multiple cases of gastric cancer. To our knowledge, there are no penetrance estimates for CDH1 without this ascertainment bias.To estimate CDH1 penetrance in a patient cohort not exclusively ascertained based on strict hereditary diffuse gastric cancer (HDGC) criteria.Retrospective review of 75 families found to have pathogenic variants in CDH1 through clinical ascertainment and multigene panel testing at a large commercial diagnostic laboratory from August 5, 2013, to June 30, 2018. CDH1 pathogenic variants were identified in 238 individuals from 75 families. Pedigrees from those families included cancer status for 1679 relatives. Penetrance estimates are based on 41 families for which completed pedigrees were available.Gastric cancer standardized incidence ratio estimates relative to Surveillance, Epidemiology, and End Results (SEER) Program incidence for pathogenic CDH1 variants from families ascertained without regard to HDGC criteria.Among the 238 individuals with a CDH1 pathogenic variant, mean (SD) age was 49.3 (18.1) years and 63.4% were female. Ethnicity was reported for 67 of 75 (89%) families; of these 67 families, 51 (76%) reported European ancestry, whereas Asian, African, Latino, and 2 or more ancestries were reported for 4 families (6%) each. Standardized incidence ratios for gastric and breast cancer were significantly elevated above SEER incidence. Extrapolated cumulative incidence of gastric cancer at age 80 years was 42% (95% CI, 30%-56%) for men and 33% (95% CI, 21%-43%) for women with pathogenic variants in CDH1, whereas cumulative incidence of female breast cancer was estimated at 55% (95% CI, 39%-68%). International Gastric Cancer Linkage Consortium criteria were met in 25 of the 75 (33%) families; however, dispensing with the requirement of confirmation of HDGC histologic subtype, 43 (57%) would meet criteria.The cumulative incidence of gastric cancer for individuals with pathogenic variants in CDH1 is significantly lower than previously described. Because prophylactic gastrectomy can have bearing upon both physical and psychological health, further discussion is warranted to assess whether this surgical recommendation is appropriate for all individuals with pathogenic variants in CDH1.
Abstract 260: Identifying cancer drug sensitivity using live cell imaging dynamic BH3 profiling of solid tumor core biopsies
Authors: Rebecca German, Elizaveta Lavrova, Timothy Hagan, Otari Chipashvili, Ewa Sicinska, James Cleary, Kimmie Ng, Anthony Letai, Patrick Bhola
Journal: Cancer Research (2019)

Abstract Given the rapid development of new small molecule cancer therapeutics, there is a growing need for predictive diagnostics to match cancer patients with optimal therapies. We previously developed a precision medicine technology with a functional phenotypic readout called dynamic BH3 profiling (DBP). DBP exposes cancer cells to drugs and measures induction of apoptotic cell death signaling after 24 hours ex vivo. Nonetheless, the application of DBP to core biopsies from metastatic tumors or other limited samples remains a technical challenge. Here, we adapt the DBP protocol for use on samples with small numbers of cells such as core biopsies. We maximize information returned per cell by imaging mitochondrial integrity in response to BH3 peptide exposure over time. We first show that the adapted protocol works in limited numbers of cancer cell lines, and in limited cells from the MMTV-PyMT genetically engineered mouse model of breast cancer. Specifically, we show that our ex vivo DBP predictions of the MMTV-PyMT mouse tumor matches known in vivo response. Finally, we apply our modified protocol to patient derived xenografts of colon cancer and primary patient colon tumors. We expect that our adapted protocol will find utility as a clinical biomarker, and as a method to optimize pre-clinical drug testing. Citation Format: Rebecca German, Elizaveta Lavrova, Timothy Hagan, Otari Chipashvili, Ewa Sicinska, James Cleary, Kimmie Ng, Anthony Letai, Patrick Bhola. Identifying cancer drug sensitivity using live cell imaging dynamic BH3 profiling of solid tumor core biopsies [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 260.
Abstract 4346: PI3K pathway mediated splicing defects in ER+ breast cancers
Authors: Erik Ladewig, Lauren Fairchild, Maurizio Scaltriti, Christina Leslie, Eneda Toska, Jose Baselga
Journal: Cancer Research (2019)

Abstract Activating mutations in PIK3CA, the gene encoding for the catalytic subunit (p100a), are the most common oncogenic alterations in estrogen receptor-positive (ER+). The majority of PIK3CA mutations occur within two hot spots; exons 9 and exon 20 which encode the helical (E545K) and kinase domains (H1047R), respectively. These mutations result in hyperactivation of the PI3K/AKT/mTOR pathway and provide the rationale for the development of inhibitors targeting the PI3K pathway. To this end, PI3K α-specific inhibitors are showing antitumor activity in patients with PIK3CA-mutant, ER-positive breast cancer. Evidence of alternative mRNA regulation and splicing in various cancers has been described in the literature. Although, the majority of events appear to have unknown clinical significance, there is evidence alternative splicing can lead to drug resistance. The role of the PI3K pathway on transcriptional regulation and mRNA processing is not well studied. Through transcriptome analysis and cell assays in mouse MEF and human MCF10A cells we demonstrate splicing defects accrue as a result of the PI3K pathway activation by the PIK3CA H1047R mutation. PI3Ka pathway inhibitors were able to restore wildtype exon inclusion levels in these mutants, suggesting a potential clinical benefit. We propose that PIK3CA H1047R imposes mRNA differential isoform regulation by acting through the most commonly mutated PI3K pathway in ER+ breast cancers and that such mutations are targetable with PI3K pathway inhibitors. Citation Format: Erik Ladewig, Lauren Fairchild, Maurizio Scaltriti, Christina Leslie, Eneda Toska, Jose Baselga. PI3K pathway mediated splicing defects in ER+ breast cancers [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 4346.
Abstract 2962: A Population-based Study Of Total Anomalous Pulmonary Venous Drainage And The Impact Of Pulmonary Venous Obstruction.
Authors: Anna N Seale, Hideki Uemura, Steve A Webber, John Partridge, Michael Roughton, Siew Y Ho, Karen P McCarthy, Sheila Jones, Lynda Shaughnessy, Jan Sunnegardh, Katarina Hanseus, H Berggren, S Johansson, Michael L Rigby, Barry R Keeton, Piers E Daubeney
Journal: Circulation (2007)

Introduction: Despite improvement in early mortality for total anomalous pulmonary venous connection (TAPVC), late mortality is frequently associated with pulmonary venous obstruction (PVO). We aim...
Abstract 2852: PKM2 phosphorylates and stabilises Matrin 3 which promotes FOXC2-mediated tumorigenesis
Authors: Richa Kumari, Sanjeev Das
Journal: Cancer Research (2019)

Abstract PKM2 is tumor specific isoform of Pyruvate kinase essential for Warburg effect. Apart from its well-known function in aerobic glycolysis, it has non-metabolic functions as well. Under oncogenic/mitogenic stimulation conditions it can translocate into the nucleus and acts as co-transactivator or kinase and promotes tumorigenesis. In order to explore its interactome we carried out a proteomic screen and found several interacting proteins. However, in vitro and in vivo studies confirmed Matrin 3 as a novel interacting partner of PKM2. Kinase assays revealed Matrin 3 as novel substrate of the PKM2-mediated phosphorylation. Further, we mapped the site of phosphorylation to the highly conserved T239 residue in Matrin 3. Intriguingly; this phosphorylation is inhibitory in nature as it prevents Matrin 3 degradation by abrogating K48-linked ubiquitylation. Moreover, the expression of a phospho-dead mutant of Matrin 3 or kinase-dead mutant of PKM2 increases ubiquitylation and leads to reduced level of Matrin 3.We also identified K132 as site of ubiquitylation which is conserved across species. Further, we screened a shRNA library targeting nuclear E3 ubiquitin ligases and identified FBXO11 as the cognate E3 ligase involved in this degradation. Matrin 3 is a RNA binding protein which mediates post-transcriptional regulation of various mRNAs. Further studies using qPCR array for EMT related genes and RNA immunoprecipitation assays established that Matrin 3 binds to FOXC2 and promotes post-transcriptional stability of FOXC2. FOXC2 is a transcription factor which regulates EMT, angiogenesis, invasion/migration by regulating Integrin β-3, ZEB1 and c-MET. Decreased Matrin 3 level leads to reduced proliferation capacity, migration and invasiveness of tumor cells. Furthermore, mouse tumor models confirmed that Matrin 3 promotes tumorigenesis, metastasis and invasion in FOXC2 dependent manner. Taken together, our findings add to the substrate repertoire of nuclear PKM2 kinase and provide key insights into FOXC2-mediated tumorigenesis. Citation Format: Richa Kumari, Sanjeev Das. PKM2 phosphorylates and stabilises Matrin 3 which promotes FOXC2-mediated tumorigenesis [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 2852.
Outcomes of pancreatic adenocarcinoma resection between initial resectable and borderline/unresectable patients undergoing neoadjuvant chemotherapy: a two-center study
Authors: J. Moreira-Pinto, J. Godinho, P. Simões, L. Leal da Costa, I. Mata, F. Branco, C. Pulido, M. Costa Santos, C. Cunha, T. Padrão, F. Lopes, J. Teixeira, T. Rodrigues, M. Casa-Nova, R. Maio, J. Passos-Coelho
Journal: Annals of Oncology (2019)
Abstract 1634: A topology based data analysis method to predict survival time
Authors: Cheng Huang, Hui-Chuan Sun, Junda Chen, Lin Shi, Fengqing Li, Yihui Lin, Hanyan Yang
Journal: Cancer Research (2019)

Abstract There are different methods to predict survival time, including traditional statistical regression, and modern neural network. Still, precise prediction of survival time remains as a challenge. In recent years algebraic topology was introduced as a novel method to infer information from high dimensional data set, where a mapper uses an algorithm to obtain geometric or topological features of the data set, and associate the features with the predicted variables. In this study, the data set includes gender, age, AFP, GGT, PPT, TB, ALT, tumor size, tumor number, BCLC stage, number of liver nodules, type of surgical approach etc., total 21 diagnostic variables. We use these variables to predicted OS and DFS, and the data set contains 329 records. In this study, the topology mapper is executed to acquire the topological features of all the data (including training and test sets), since this task is unsupervised, so the target values are not considered. Our method is to infer three new features of each data record, including the location of the record on the main branch of the topology, whether it is a branch node (i.e. has more than 2 branches), and whether it is an endpoint. A simple neural network with one hidden layer is designed and implemented with Tensorflow, and the three features will be added to the data set and provide valuable information for prediction of the target values. Without adding the new features from topology mapper, we have 72% accuracy (in predicting the survival time is greater or less than the mean value) on test set data when predicting OS, and we have 75% accuracy on test set data when predicting the DFS. With the new features from topology mapper, we have 83% accuracy on test set data when predicting OS, and 84% accuracy on test set data when predicting the DFS. The three new features inferred from the topology mapper have a significant effect on the accuracy of prediction and provide better accuracy. The topology based data analysis method in this study could be applied to other classification problems related to clinical trial data, and will need further verification. Citation Format: Cheng Huang, Hui-Chuan Sun, Junda Chen, Lin Shi, Fengqing Li, Yihui Lin, Hanyan Yang. A topology based data analysis method to predict survival time [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 1634.
Abstract LB-198: Discovery of a novel anti-CD47 antibody with anti-cancer therapeutic potential and minimal RBC binding
Authors: Xiao Feng, Dawei Sun, Suofu Qin, Lei Jin, Tao Wang, Hongbo Yan
Journal: Cancer Research (2019)

Abstract CD47 is a widely expressed cell surface protein that functions as a checkpoint in the immune system. When overexpressed on tumor cells, CD47 can bind SIRPα on myeloid cells, leading to suppression of tumor cell phagocytosis and other innate immune functions. Thus, targeting CD47 is becoming a hot spot of cancer immunotherapy. However, its ubiquitous expression on circulating cells, especially RBCs and hepatocyte, poses a safety concern in CD47 targeted therapy.In this study, we discovered a novel anti-CD47 antibody, GenSci-059. GenSci-059 exhibited equivalent anticancer effects with Hu5F9-G4, a humanized anti-CD47 antibody in clinical trial, evidenced by inducing significant phagocytosis of tumor cells in vitro and prolonging the survival of xenografted mice. Especially for non-Hodgkin’s lymphoma (NHL), GenSci-059 showed almost 100% tumor growth inhibition with 100% response rate in the patient-derived xenograft (PDX) NHL models tested. Remarkably, GenSci-059 did not bind to human RBCs and induced minimal RBC phagocytosis by in vitro assay. In cynomolgus monkeys, GenSci-059 was well tolerated at doses up to 300 mg/kg, and did not produce adverse effects including anemia and hepatic dysfunction, which are common side effects of other anti-CD47 therapies. Overall, GenSci-059 is a promising candidate with great potential and safety profile for cancer immunotherapy. Citation Format: Xiao Feng, Dawei Sun, Suofu Qin, Lei Jin, Tao Wang, Hongbo Yan. Discovery of a novel anti-CD47 antibody with anti-cancer therapeutic potential and minimal RBC binding [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 LB-198.
Coevolution of Sites under Immune Selection Shapes Epstein–Barr Virus Population Structure
Authors: Fanny Wegner, Florent Lassalle, Daniel P Depledge, François Balloux, Judith Breuer
Journal: Molecular Biology and Evolution (2019)

Epstein-Barr virus (EBV) is one of the most common viral infections in humans and persists within its host for life. EBV therefore represents an extremely successful virus that has evolved complex strategies to evade the host's innate and adaptive immune response during both initial and persistent stages of infection. Here, we conducted a comparative genomics analysis on 223 whole genome sequences of worldwide EBV strains. We recover extensive genome-wide linkage disequilibrium (LD) despite pervasive genetic recombination. This pattern is explained by the global EBV population being subdivided into three main subpopulations, one primarily found in East Asia, one in Southeast Asia and Oceania, and the third including most of the other globally distributed genomes we analyzed. Additionally, sites in LD were overrepresented in immunogenic genes. Taken together, our results suggest that host immune selection and local adaptation to different human host populations has shaped the genome-wide patterns of genetic diversity in EBV.
Burden and Causes of Hospital Admissions in Heart Failure During the Last Year of Life
Authors: Christian Madelaire, Finn Gustafsson, Søren L. Kristensen, Maria D’Souza, Lynne W. Stevenson, Lars Kober, Christian Torp-Pedersen, Gunnar Gislason, Morten Schou
Journal: JACC Heart Failure (2019)