tbuckley/cabot-search huggingface dataset:
Abstract P217: Nuclear Protein Import as the Missing Link in Phenylephrine-Induced Cardiomyocyte Hypertrophy
Authors: Mirna N Chahine, Maxime Mioulane, Gabor Földes, Alexander Lyon, Sian E Harding
Journal: Circulation Research (2011)

During cardiac hypertrophy, cardiomyocytes (CM) present alterations in gene expression and increased contractile protein content. Nuclear protein import (NPI) is critical in regulating gene expression, transcription, and subsequently cell hypertrophy. However, it is unknown how the nuclear transport machinery (transport receptors and nuclear pore complex (NPC)) functions to sustain increased demands for nucleocytoplasmic trafficking. The aim of this study was to determine if exposure of adult CM to phenylephrine (PE) affects hypertrophy by altering NPI and NPC density. Comparisons were made to adult failing rat and human CM. Rat myocytes were enzymatically isolated from adult hearts, and used for immunocytochemistry, qPCR and western immunoblotting. Failing CM were obtained from explanted human hearts at the time of transplant and from a rat model of myocardial infarction-induced hypertrophy and failure. Rat adult CM exposed for 48h to PE were injected with a protein import substrate (Alexa488-BSA-NLS) to visually monitor nuclear import with the confocal microscope. The effects of P38 MAPK inhibitor, HDAC inhibitor, Exportin-1 (CRM-1) inhibitor, and GSK-3 β inhibitor were investigated. Cell and nuclear sizes were increased in PE treated-adult rat CM and in the adult failing rat and human CM compared to normal CM. In contrast, PE depressed the rate and maximal NPI (by 65 +/- 3.4 % (3.55 from 5.46), p&lt;0.05) as well as nucleoporin p62 mRNA and protein expression levels in adult rat CM compared to non-treated CM. Nucleoporin p62, cytoplasmic Ranbp1, and nuclear translocation of importins (Imp.α and β) relative densities were also decreased in PE treated-adult rat CM and in adult failing rat CM and human heart tissue compared to normal controls. On the contrary, CRM-1 nuclear export relative density was increased during the same pathological conditions. Thus NPI downregulation is linked to an increased nuclear export required by CM to generate the hypertrophic phenotype. All these effects were P38MAPK, HDAC and CRM-1 dependent but GSK-3Beta independent in rat CM. Our results show that alterations in NPI and NPC density occur in failing CM as well as in CM under hypertrophic stimuli. NPI may represent a critical therapeutic target in hypertrophic conditions.
Update: Influenza Activity in the United States During the 2017–18 Season and Composition of the 2018–19 Influenza Vaccine
Authors: Rebecca Garten, Lenee Blanton, Anwar Isa Abd Elal, Noreen Alabi, John Barnes, Matthew Biggerstaff, Lynnette Brammer, Alicia P Budd, Erin Burns, Charisse N Cummings, Todd Davis, Shikha Garg, Larisa Gubareva, Yunho Jang, Krista Kniss, Natalie Kramer, Stephen Lindstrom, Desiree Mustaquim, Alissa O'Halloran, Wendy Sessions, Calli Taylor, Xiyan Xu, Vivien G Dugan, Alicia M Fry, David E Wentworth, Jacqueline Katz, Daniel Jernigan
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

The United States 2017-18 influenza season (October 1, 2017-May 19, 2018) was a high severity season with high levels of outpatient clinic and emergency department visits for influenza-like illness (ILI), high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity across the country for an extended period. Nationally, ILI activity began increasing in November, reaching an extended period of high activity during January-February, and remaining elevated through March. Influenza A(H3N2) viruses predominated through February and were predominant overall for the season; influenza B viruses predominated from March onward. This report summarizes U.S. influenza activity* during October 1, 2017-May 19, 2018.†.
Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment
Authors: Ya-Ting Wang, Jocelyn Chen, Chou-Wei Chang, Jayu Jen, Tzu-Yu Huang, Chun-Ming Chen, Roger Shen, Suh-Yuen Liang, I-Cheng Cheng, Shuenn-Chen Yang, Wu-Wei Lai, Kuang-Hung Cheng, Tao-Shih Hsieh, Ming-Zong Lai, Hung-Chi Cheng, Yi-Ching Wang, Ruey-Hwa Chen
Journal: Journal of Clinical Investigation (2017)

The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4). Clinically, this PML degradation pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell-surface or secreted factors, including CD73, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. In xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth. These immunosuppressive effects were all reversed by CD73 blockade. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment, suggesting the potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.
Hi-C as a tool for precise detection and characterisation of chromosomal rearrangements and copy number variation in human tumours
Authors: Louise Harewood, Kamal Kishore, Matthew D. Eldridge, Steven Wingett, Danita Pearson, Stefan Schoenfelder, V. Peter Collins, Peter Fraser
Journal: Genome biology (2017)

Chromosomal rearrangements occur constitutionally in the general population and somatically in the majority of cancers. Detection of balanced rearrangements, such as reciprocal translocations and inversions, is troublesome, which is particularly detrimental in oncology where rearrangements play diagnostic and prognostic roles. Here we describe the use of Hi-C as a tool for detection of both balanced and unbalanced chromosomal rearrangements in primary human tumour samples, with the potential to define chromosome breakpoints to bp resolution. In addition, we show copy number profiles can also be obtained from the same data, all at a significantly lower cost than standard sequencing approaches.
Role of Polycomb Repressors in Stem Cells, Cancer, and Development
Authors: Maarten Lohuizen
Journal: Clinical Cancer Research (2007)

PL03-03  Repressive Polycomb-group (Pc-G) protein complexes and the counteracting Trithorax-group (Trx-G) of nucleosome remodeling factors are involved in the dynamic maintenance of proper gene expression patterns during development, acting at the level of chromatin structure. As such, they are important controllers of cell fate. When deregulated, these master switches of gene expression are strongly implicated in formation of a diverse set of cancers. An example is the Pc-G gene Bmi1 which is overexpressed in medulloblastoma, Non small cell lung cancer, hepatocellular carcinoma and breast cancer and Glioma and is causally implicated in leukemia. We and others have recently implicated Bmi1/Pc-G as a critical regulator of stem cell fate in hemapoietic stem cells, neural stem cells, mammary epithelial precursor cells and ES cells. In addition, we have shown that Bmi1 is regulated by the Shh pathway and that the Ink4a/ARF tumors suppressors are critical Bmi1 target genes in stem cells and in cancer formation. However our recent work on brain cancer (Glioma) points to important ink4a/ARF-independent Bmi1 targets involved in adhesion and motility. Comprehensive profiling of Polycomb target genes in Drosophila revealed its crucial conserved role in repressing lineage differentiation pathways and morphogens, including Wg, Hh, Delta and Notch. Furthermore, we have characterized in detail an essential E3-ubiquitin ligase activity in the PRC1 Polycomb complex that consists of a functional Ring1B-Bmi1 heterodimer. This E3 ligase activity is required for maintenance of Polycomb repression in normal- and cancer stem cells and hence offers potential novel ways to target cancer stem cells or tumor re-initiating cells in which the activity of this E3 ligase is hyperactivated. This is further substantiated by a novel way by which the activity of the Ring1B.Bmi1 E3 ligase is controlled. The implications of these findings for stem cell biology, development and cancer will be discussed.
Resistance to the Antibody–Drug Conjugate T-DM1 Is Based in a Reduction in Lysosomal Proteolytic Activity
Authors: Carla Ríos-Luci, Sara García-Alonso, Elena Díaz-Rodríguez, Mercedes Nadal-Serrano, Joaquín Arribas, Alberto Ocaña, Atanasio Pandiella
Journal: Cancer Research (2017)

Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that was approved recently to treat HER2+ breast cancers. Despite its impressive clinical efficacy in many patients, intrinsic and acquired resistance to T-DM1 has emerged as a challenge. To identify mechanisms of T-DM1 resistance, we isolated several resistant HER2+ clones exhibiting stable drug refractoriness in vitro and in vivo Genomic comparisons showed substantial differences among three of the isolated clones, indicating several potential mechanisms of resistance to T-DM1. However, we observed no differences in HER2 levels and signaling among the resistant models and parental HER2+ cells. Bioinformatics studies suggested that intracellular trafficking of T-DM1 could underlie resistance to T-DM1, and systematic analysis of the path followed by T-DM1 showed that the early steps in the internalization of the drug were unaltered. However, in some of the resistant clones, T-DM1 accumulated in lysosomes. In these clones, lysosomal pH was increased and the proteolytic activity of these organelles was deranged. These results were confirmed in T-DM1-resistant cells from patient-derived HER2+ samples. We postulate that resistance to T-DM1 occurs through multiple mechanisms, one of which is impaired lysosomal proteolytic activity. Because other ADC may use the same internalization-degradation pathway to deliver active payloads, strategies aimed at restoring lysosomal functionality might overcome resistance to ADC-based therapies and improve their effectiveness. Cancer Res; 77(17); 4639-51. ©2017 AACR.
Multitasking and Silent Electronic Health Record Use in Ambulatory Visits
Authors: Neda Ratanawongsa, George Y. Matta, Courtney R. Lyles, Christopher J. Koenig, Jennifer L. Barton, Kaylin Yu, Dean Schillinger
Journal: JAMA Internal Medicine (2017)

Author(s): Ratanawongsa, Neda; Matta, George Y; Lyles, Courtney R; Koenig, Christopher J; Barton, Jennifer L; Yu, Kaylin; Schillinger, Dean
Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet—a population-based study
Authors: Gemma Gatta, Riccardo Capocaccia, Laura Botta, Sandra Mallone, Roberta De Angelis, Eva Ardanaz, Harry Comber, Nadya Dimitrova, Maarit K Leinonen, Sabine Siesling, Jan M van der Zwan, Liesbet Van Eycken, Otto Visser, Maja P Žakelj, Lesley A Anderson, Francesca Bella, Innos Kaire, Renée Otter, Charles A Stiller, Annalisa Trama, Monika Hackl, Kris Henau, Nancy Van Damme, Zdravka Valerianova, Mario Sekerija, Ladislav Dušek, Margit Mägi, Keiu Paapsi, Nea Malila, Michel Velten, Xavier Troussard, Veronique Bouvier, Anne-Valérie Guizard, Anne-Marie Bouvier, Patrick Arveux, Marc Maynadié, Anne-Sophie Woronoff, Michel Robaszkiewicz, Isabelle Baldi, Alain Monnereau, Brigitte Tretarre, Marc Colonna, Florence Molinié, Simona Bara, Claire Schvartz, Bénédicte Lapôtre-Ledoux, Pascale Grosclaude, Roland Stabenow, Sabine Luttmann, Alice Nennecke, Jutta Engel, Gabriele SchubertFritschle, Jan Heidrich, Bernd Holleczek, Jón Gunnlaugur Jónasson, Kerri Clough-Gorr, Guido Mazzoleni, Adriano Giacomin, Antonella Sutera Sardo, Alessandro Barchielli, Diego Serraino, Paolo Collarile, Fabio Pannozzo, Paolo Ricci, Mariangela Autelitano, Gianbattista Spagnoli, Mario Fusco, Mario Usala, Francesco Vitale, Maria Michiara, Rosario Tumino, Lucia Mangone, Fabio Falcini, Stefano Ferretti, Rosa Angela Filiberti, Enza Marani, Anna Luisa Caiazzo, Arturo Iannelli, Flavio Sensi, Silvano Piffer, Maria Gentilini, Anselmo Madeddu, Antonino Ziino Colanino, Sergio Maspero, Pina Candela, Fabrizio Stracci, Giovanna Tagliabue, Massimo Rugge, Paolo Baili, Pamela Minicozzi, Milena Sant, Carmen Tereanu, Silvia Francisci, Andrea Tavilla, Daniela Pierannunzio, Silvia Rossi, Mariano Santaquilani, Arnold Knijn, Santa Pildava, Giedre Smailyte, Neville Calleja, Dominic Agius, Tom Børge Johannesen, Jadwiga Rachtan, Stanislaw Gózdz, Jerzy Blaszczyk, Kamila Kepska, Gonçalo Forjaz de Lacerda, Maria José Bento, Ana Miranda, Chakameh Safaei Diba, Tina Žagar, Enrique Almar, Nerea Larrañaga, Arantza Lopez de Munain, Ana Torrella-Ramos, José María Díaz García, Rafael Marcos-Gragera, Maria Josè Sanchez, Carmen Navarro, Diego Salmeron, Conchi Moreno-Iribas, Jaume Galceran, Marià Carulla, Mohsen Mousavi, Christine Bouchardy, Silvia M. Ess, Andrea Bordoni, Isabelle Konzelmann, Jem Rashbass, Anna Gavin, David H Brewster, Dyfed Wyn Huws, Vincent KY Ho, Ellen Benhamou
Journal: The Lancet Oncology (2017)
Prevalence and Evolution of Hypertransaminasemia in the Newly Diagnosed Coeliac Patients: An Irish Experience in a Dublin Hospital
Authors: SG Veerappan, CA O'Morain, BM Ryan
Journal: Endoscopy (2006)

Aims: To evaluate the prevalence of hypertransaminasemia (ALT) in coeliac patients presenting to a Dublin hospital and the activity of ALT after a gluten free diet (GFD).
Raw milk consumption and other early-life farm exposures and adult pulmonary function in the Agricultural Lung Health Study
Authors: Annah B Wyss, John S House, Jane A Hoppin, Marie Richards, John L Hankinson, Stuart Long, Paul K Henneberger, Laura E Beane Freeman, Dale P Sandler, Elizabeth Long O’Connell, Christie Barker Cummings, David M Umbach, Stephanie J London
Journal: Thorax (2017)

Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher FEV1 (β=49.5 mL, 95% CI 2.8 to 96.1 mL, p=0.04) and FVC (β=66.2 mL, 95% CI 13.2 to 119.1 mL, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood.
Abstract 114: AdipoRon, the First Orally Active Adiponectin Receptor Activator, Attenuates Post-ischemic Myocardial Apoptosis via AMPK Activation and Oxidative Stress Reduction
Authors: Yajing Wang, Wayne Lau, Yuanhui Du, Erhe Gao, Walter Koch, Xinliang (Xin) Ma
Journal: Circulation Research (2015)

Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild type (WT) or gene manipulated mice were treated with vehicle or AdipoRon (50 mg/kg, 10 minutes prior to MI) and subjected to MI/R (30 minutes/3-24 hours). Oral administration of AdipoRon to WT mice significantly improved cardiac function (P&lt;0.01) and reduced infarct size (P&lt;0.01). At cellular level, AdipoRon attenuated post-ischemic cardiomyocyte apoptosis determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (P&lt;0.01). MI/R-induced apoptotic cell death was significantly enhanced in APN deficient mice (APNKO), and AdipoRon attenuated MI/R injury to the same degree observed in WT mice, indicating the pathological exageration caused by APN deficience can be rescured by a small molecule APN receptor activator. Cardiomyocyte-specific inhibition of AMPK (AMPK-DN), the most significant molecule mediating APN’s metabolic regulatory function, also increased post-ischemic apoptosis. Interestingly, AdipoRon’s anti-apoptotic action was partially inhibited, but not lost in AMPK-DN mice, indicating the anti-apoptotic effect of AdipoRon cannot be completely atributed to AMPK activation. AdipoRon significantly attenuated post-ischemic oxidative stress in an AMPK-independent fashion, as evidenced by reduced NADPH oxidase expression and superoxide production in both WT and AMPK-DN mice. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated post-ischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.
Identification of differentially expressed genes associated with clinical response after treatment of breast cancer skin metastases with imiquimod.
Authors: Mariya Rozenblit, Adriana Heguy, Luis Chiriboga, Cynthia Loomis, Farbod Darvishian, Mikala Egeblad, Yongzhao Shao, Sylvia Adams
Journal: Journal of Clinical Oncology (2017)

e12541 Background: Imiquimod, a Toll-like receptor 7 agonist, activates innate immunity and has a response rate of 20% in breast cancer skin metastases. Tumor regression is associated with increased tumor infiltrating lymphocytes and increased Th1 cytokines in tumor supernatant, however gene expression changes are unknown. This is the first report of gene expression changes induced by imiquimod treatment in breast cancer skin metastases. Methods: FFPE-extracted mRNA from 8 patients pre and post 8 weeks of imiquimod treatment was analyzed using Nanostring PanCancer Immune Profiling Panel. Gene expression and pathway analysis was conducted with nSolver 3.0 with clinical response as outcome, controlling for HER2 ER/PR status, with 5% significance level used. Results: In all patients, imiquimod was associated with upregulation of genes in innate immunity such as TLR7, IL-1, T-cell, B-cell, and NK related genes. Three patients had a clinical response after imiquimod. Forty-two differentially expressed genes were identified in responders vs. non-responders after imiquimod. Reponders had up-regulation of T cell (CD2, SPN), NK cell (KLRC2), B cell (CD48), lymphocyte (LY96), and IL-2 (IL2RG) related genes. The top upregulated pathways were cytotoxicity, NK cell function, and antigen processing. Pre-treatment, the responders had upregulation of TNF and IL-17 related genes (TNFRSF10B, IL17RA) compared to non-responders. Comparing pre-treatment to post-treatment, Imiquimod was associated with mRNA expression changes in 72 genes in responders vs non responders. The top upregulated genes involved activation of lymphocytes (SH2D1A), NK cells (KLRC2), DCs (CLEC4C), several chemokines, IL7R and immune regulators PLD1 and IRF5. Conclusions: Clinical response to Imiquimod treatment of breast cancer skin metastases is associated with upregulation of genes in innate immunity suggestive of an anti-tumor immune response. Inhibition of negative feedback by addition of PLD1 inhibitors may enhance treatment response. Understanding the genetic signature of imiquimod can enhance prediction of response and inform possible combination therapies in the future.
Heavy+light chain monitoring correlates with clinical outcome in multiple myeloma patients
Authors: M Michallet, C Chapuis-Cellier, T Dejoie, C Lombard, H Caillon, M Sobh, P Moreau, M Attal, H Avet-Loiseau
Journal: Leukemia (2017)

Novel anti-myeloma agents have improved patient response rates, which are historically based on reductions of the M-protein. These methods can be inaccurate for quantifying M-proteins at low concentrations. We compared the consistency and clinical impact of response assignment by electrophoretic and heavy+light chain (HLC) immunoassays post-consolidation in 463 newly diagnosed patients. The two methods gave similar assignments in patients with partial (PR; 79% agreement) or complete response (⩾CR; 92%). However, in patients achieving very good PR (VGPR) there was poor concordance between methods (45%). Median progression-free survival (PFS) for standard VGPR patients was 34.5 months; HLC responses stratified these patients further into PR, VGPR and ⩾CR, with median PFS of 21.3, 28.9 months and not reached, respectively; P<0.001. At this time, abnormal HLC ratios had better concordance with multiparametric flow cytometry (sensitivity 10−4) (37 and 34% positive, respectively), compared to immunofixation (62% positive). In addition, HLC-pair suppression was identified in 38% of patients and associated with shorter PFS (30.6 months vs not reached; P<0.001). We conclude that HLC monitoring could augment electrophoretic assessments in patients achieving VGPR. The prognostic significance of HLC responses might partly depend on the patients' ability to recover their immune system, as determined by normalisation of HLC measurements.
Submucosal fibrosis in achalasia patients is a rare cause of aborted peroral endoscopic myotomy procedures
Authors: Qiu-Ning Wu, Xiao-Yue Xu, Xiao-Cen Zhang, Mei-Dong Xu, Yi-Qun Zhang, Wei-Feng Chen, Ming-Yan Cai, Wen-Zheng Qin, Jian-Wei Hu, Li-Qing Yao, Quan-Lin Li, Ping-Hong Zhou
Journal: Endoscopy (2017)

Abstract Background and aims Peroral endoscopic myotomy (POEM) is now an established treatment for esophageal achalasia. The standard protocol ensures a smooth operation in most patients, but technical challenges and failures exist and little is known about the incidence, causes, and impact of aborted procedures. Here, using a large patient cohort, we attempted to answer these questions. Methods All patients admitted for planned POEM between August 2010 and July 2015 underwent chart review. Aborted POEM was defined as the inability to finish the procedure after submucosal injection. The cause of the failure, clinical course, management, and follow-up data were analyzed. Results Thirteen of the 1693 POEMs (0.77 %) were aborted. Out of the 13 failures, 12 (92.3 %) were due to severe submucosal fibrosis, which precluded tunneling, and one (7.7 %) was due to atrial fibrillation related to the electric current of the endoscopic knife. Submucosal fibrosis, prior Heller myotomy, and age ( ≥ 60 years) were related to technical failure, while a disease duration of ≥ 6 years, sigmoid esophagus, mucosal edema, and prior interventions were risk factors for the presence of fibrotic changes. In turn, fibrosis was correlated with a prolonged operation, longer hospital stay, more mucosal injuries, and more major perioperative adverse events. Finally, the yearly frequency of aborted POEMs decreased after the second year as operators became more experienced. Conclusions Aborted POEM is a rare event and is largely due to the presence of submucosal fibrosis, which not only causes increased procedural difficulties, but also gives rise to major adverse events.