tbuckley/cabot-search huggingface dataset:
Abstract B25: HNRNPH1-dependent splicing of the fusion oncogene <i>EWS-FLI1</i> reveals a targetable RNA G-quadruplex interaction
Authors: Carla Neckles, Robert E. Boer, Nicholas Aboreden, Allison M. Cross, Robert L. Walker, Bong-Hyun Kim, Suntae Kim, John S. Schneekloth, Natasha J. Caplen
Journal: Cancer Research (2020)

Abstract The primary oncogenic event in ~85% of Ewing sarcomas is a chromosomal translocation that generates a fusion gene encoding an aberrant transcription factor EWS-FLI1. In a third of EWS-FLI1 driven tumors, translocations that retain exon 8 of EWSR1 must exclude this exon to synthesize a protein-encoding mRNA. We have previously demonstrated that the heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) binds to G-rich sequences within EWSR1 exon 8 and that this binding event is required to express an in-frame EWS-FLI1 mature mRNA. G-rich nucleic acids may fold into stable tertiary structures, such as RNA guanine quadruplexes (rG4s). Our current studies are focused on the tertiary RNA structure of the G-rich regions within EWSR1 exon 8 and its role in HNRNPH1-dependent RNA processing. Here, we show that the processing of distinct EWS-FLI1 pre-mRNAs by HNRNPH1, but not other homologous family members, resembles alternative splicing of rare transcript variants of wild-type EWSR1. We demonstrate that guanine-rich sequences within EWSR1 exon 8 can fold into RNA G-quadruplex structures and that HNRNPH1 preferentially binds these RNAs when in a folded state. Critically, we also demonstrate that transfection of a single-stranded RNA oligomer corresponding to one of these G-rich sequences (rG1) reduces the expression of EWS-FLI1 mRNA and EWS-FLI1 protein and decreases its transcriptional activity. Small molecules that can displace HNRNPH1 binding may provide a therapeutic vulnerability in a subset of Ewing sarcoma. To evaluate if this protein-RNA interaction is amenable to small molecules, we performed displacement assays with HNRNPH1 protein and an EWSR1 exon 8 RNA oligomer (rG1) at varying concentrations of a G4-binding molecule, pyridostatin (PDS). We found that PDS disrupts the formation of the HNRNPH1-rG1 complex (IC50 of 7 micromolar). Furthermore, treatment with PDS selectivity inhibits the growth of Ewing sarcoma cell lines harboring EWSR1 exon 8 fusions, decreases EWS-FLI1 activity in cell-based reporter assays, and restores mRNA expression of EWS-FLI1 deregulated transcriptional targets. Our findings illustrate that modulation of the alternative splicing of EWS-FLI1 pre-mRNA is a promising strategy for future therapeutics against this fusion oncogene expressed in a third of Ewing sarcoma. Citation Format: Carla Neckles, Robert E. Boer, Nicholas Aboreden, Allison M. Cross, Robert L. Walker, Bong-Hyun Kim, Suntae Kim, John S. Schneekloth, Natasha J. Caplen. HNRNPH1-dependent splicing of the fusion oncogene EWS-FLI1 reveals a targetable RNA G-quadruplex interaction [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B25.
Abstract A57: Feasibility of physical activity in children with cancer: A multidisciplinary program in the context of the VIE study
Authors: Maxime Caru, Gabrielle Duhamel, Valérie Marcil, Serge Sultan, Caroline Meloche, Isabelle Bouchard, Simon Drouin, Laurence Bertout, Caroline Laverdière, Daniel Sinnett, Daniel Curnier
Journal: Cancer Research (2020)

Abstract Purpose: Cancer is one of the leading causes of death in the world. The physiologic and psychological benefits of physical activity have been shown in children with cancer. However, almost one in two cancer patients do not follow the physical activity guidelines. The aim of this study will be to assess the feasibility of a physical activity program intervention in pediatric oncology and to assess the barriers and facilitators in the success or failure of this physical activity program. Methods: The VIE (Valorization, Implication and Education) intervention is a multidisciplinary program including physical activity, nutritional, and psychological interventions in pediatric oncology. This study involves one intervention group that will be followed over two years (evaluations and physical activity interventions) and one control group that will participate in only one evaluation. The feasibility of this program will be measured through a comparison between sessions performed and sessions scheduled, while the security will be measured according to the number of reported incidents. Preliminary Results: An adhesion rate of about 40% despite restrictions and organizational conflicts specific to the hospital context was reported. A minor incident in 1 of 278 sessions performed with 35 children with cancer was observed. Conclusion: This study is the first to examine the effects of exercise in pediatric oncology, from diagnosis to the expected end of treatment. At this time, our findings show the feasibility of this physical activity program in a safe context. This is an important study in the exercise and oncology field to help patients and their family during and after cancer treatments. Citation Format: Maxime Caru, Gabrielle Duhamel, Valérie Marcil, Serge Sultan, Caroline Meloche, Isabelle Bouchard, Simon Drouin, Laurence Bertout, Caroline Laverdière, Daniel Sinnett, Daniel Curnier. Feasibility of physical activity in children with cancer: A multidisciplinary program in the context of the VIE study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A57.
Evaluation of Overall Survival in Patients With Anaplastic Thyroid Carcinoma, 2000-2019
Authors: Anastasios Maniakas, Ramona Dadu, Naifa L. Busaidy, Jennifer R. Wang, Renata Ferrarotto, Charles Lu, Michelle D. Williams, G. Brandon Gunn, Marie-Claude Hofmann, Gilbert Cote, Jared Sperling, Neil D. Gross, Erich M. Sturgis, Ryan P. Goepfert, Stephen Y. Lai, Maria E. Cabanillas, Mark Zafereo
Journal: JAMA Oncology (2020)

<h3>Importance</h3> Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent major advancements in treatment and OS has yet to be evaluated. <h3>Objective</h3> To evaluate rates of OS in patients with ATC over the last 2 decades. <h3>Design, Setting, and Participants</h3> Retrospective cohort study in a single tertiary care institution. Patients with histopathological confirmation of ATC from January 2000 to October 2019 were included and divided into 3 groups according to date of presentation: 2000-2013, 2014-2016, and 2017-2019. <h3>Main Outcomes and Measures</h3> Overall survival compared among different treatment eras and differing therapies, including targeted therapy, immunotherapy, and surgery. <h3>Results</h3> Of 479 patients (246 men [51%]; median age, 65.0 [range, 21.1-92.6] years) with ATC evaluated, 52 (11%) were stage IVA, 172 (36%) stage IVB, and 255 (53%) stage IVC at presentation. The median OS of the entire cohort was 0.79 years (9.5 months), ranging from 0.01 to 16.63. The OS at 1 and 2 years was 35% (95% CI, 29%-42%) and 18% (95% CI, 13%-23%) in the 2000-2013 group (n = 227), 47% (95% CI, 36%-56%) and 25% (95% CI, 17%-34%) in the 2014-2016 group (n = 100), and 59% (95% CI, 49%-67%) and 42% (95% CI, 30%-53%) in the 2017-2019 group (n = 152), respectively (<i>P</i> &lt; .001). The hazard ratio was 0.50 (95% CI, 0.38-0.67) for the 2017-2019 group compared with the 2000-2013 patients (<i>P</i> &lt; .001). Factors associated with improved OS included targeted therapy (hazard ratio, 0.49; 95% CI, 0.39-0.63;<i>P</i> &lt; .001), the addition of immunotherapy to targeted therapy (hazard ratio, 0.58; 95% CI, 0.36-0.94;<i>P</i> = .03), and surgery following neoadjuvant BRAF-directed therapy (hazard ratio, 0.29; 95% CI, 0.10-0.78;<i>P</i> = .02). Patients undergoing surgery following neoadjuvant BRAF-directed therapy (n = 20) had a 94% 1-year survival with a median follow-up of 1.21 years. <h3>Conclusion and Relevance</h3> In this large single-institution cohort study spanning nearly 20 years, changes in patient management appear to be associated with significant increase in survival. The era of untreatable ATC is progressively being replaced by molecular-based personalized therapies, with integration of multidisciplinary therapies including surgery and radiation therapy.
Abstract 166: Insertion or Replacement of an Advanced Airway is Not Associated With Adverse Outcome in Neonatal Intensive Care Unit Cardiopulmonary Resuscitation
Authors: Kaashif A Ahmad, Christina N Stine, Jaclyn M LeVan, Katy L Kohlleppel, Steven G Velasquez, Cody L Henderson, Utpal S Bhalala
Journal: Circulation (2018)

Introduction: There is a paucity of data regarding variables that impact the outcome in patients who require cardiopulmonary resuscitation (CPR) in the neonatal intensive care unit (NICU). The impact of initial need or replacement of an existing advanced airway (AA) has not been described in this population. The 2016 Neonatal Resuscitation Program (NRP) places emphasis on AA placement prior to initiating compressions in the delivery room setting. We hypothesized that providers would similarly emphasize airway placement for NICU CPR. Methods: We conducted a retrospective review of patients requiring CPR with chest compressions from 2012 to 2017 across 10 NICUs in San Antonio, Texas. We identified cases by clinician selection of a CPR code and by a review of all patients who died prior to NICU discharge. Results: We review a total of 211 NICU CPR events, 210 of which had complete data regarding the AA. An AA was present at the onset of CPR for 179 (85.2%) of CPR events and an existing airway replaced during CPR for 31 (14.7%) CPR events. All patients without an AA present at onset of CPR had an airway immediately placed. The median time to insertion of AA was 1 minute (IQR 1, 5 minutes). In comparing patients who had an AA present at CPR onset versus absent AA, there was no significant difference in rate of return of spontaneous circulation (ROSC, 63.7% vs 64.5%, p=0.92) or time to ROSC (10.2 vs 12.7 min, p=.66). The median time for replacement of an AA during CPR was 1 minute (IQR 1, 4 minutes). Those with a time to replace the AA of &gt;= 5 minutes had a similar ROSC rate compared to those who had AA replacement in &lt; 5 minutes (75% vs 73.7%, p=.96). The decision to replace an AA during CPR was associated with a non-significant increase in rate of ROSC (74.2% vs 62%, p=0.19) and no significant difference in time to ROSC (11.5 min vs. 10.4 min, p=0.65). Conclusions: The achievement of ROSC or time to ROSC are not impacted by the need to place an initial AA at the onset of CPR or the need to replace the AA during CPR in the NICU. This may be due to the rapid initial placement and replacement of the AA observed in NICU CPR events. These data indicate that NICU CPR providers emphasize rapid AA placement similar to NRP guidelines.
Galactosylated chitosan-modified ethosomes combined with silk fibroin nanofibers is useful in transcutaneous immunization
Authors: Xingxing Yang, Xiaoyun Wang, Huoyan Hong, Gomaa Elfawal, Si Lin, Jinglei Wu, Yuxin Jiang, Chuanglong He, Xiumei Mo, Guoyin Kai, Hongsheng Wang
Journal: Journal of Controlled Release (2020)
Intravascular Hemolysis Leads to Increased Esophagus Smooth Muscle Contractions in Mice: Implication for Dysphagia and Odynophagia
Authors: Fabio H Silva, Eduardo C Alexandre, Fabiano B Calmasini, Carla Fernanda Franco-Penteado, Edson Antunes, Kleber Yotsumoto Fertrin, Fernando Ferreira Costa
Journal: Blood (2017)
Multiomic Analysis of Subtype Evolution and Heterogeneity in High-Grade Serous Ovarian Carcinoma
Authors: Ludwig Geistlinger, Sehyun Oh, Marcel Ramos, Lucas Schiffer, Rebecca S. LaRue, Christine M. Henzler, Sarah A. Munro, Claire Daughters, Andrew C. Nelson, Boris J. Winterhoff, Zenas Chang, Shobhana Talukdar, Mihir Shetty, Sally A. Mullany, Martin Morgan, Giovanni Parmigiani, Michael J. Birrer, Li-Xuan Qin, Markus Riester, Timothy K. Starr, Levi Waldron
Journal: Cancer Research (2020)

Abstract Multiple studies have identified transcriptome subtypes of high-grade serous ovarian carcinoma (HGSOC), but their interpretation and translation are complicated by tumor evolution and polyclonality accompanied by extensive accumulation of somatic aberrations, varying cell type admixtures, and different tissues of origin. In this study, we examined the chronology of HGSOC subtype evolution in the context of these factors using a novel integrative analysis of absolute copy-number analysis and gene expression in The Cancer Genome Atlas complemented by single-cell analysis of six independent tumors. Tumor purity, ploidy, and subclonality were reliably inferred from different genomic platforms, and these characteristics displayed marked differences between subtypes. Genomic lesions associated with HGSOC subtypes tended to be subclonal, implying subtype divergence at later stages of tumor evolution. Subclonality of recurrent HGSOC alterations was evident for proliferative tumors, characterized by extreme genomic instability, absence of immune infiltration, and greater patient age. In contrast, differentiated tumors were characterized by largely intact genome integrity, high immune infiltration, and younger patient age. Single-cell sequencing of 42,000 tumor cells revealed widespread heterogeneity in tumor cell type composition that drove bulk subtypes but demonstrated a lack of intrinsic subtypes among tumor epithelial cells. Our findings prompt the dismissal of discrete transcriptome subtypes for HGSOC and replacement by a more realistic model of continuous tumor development that includes mixtures of subclones, accumulation of somatic aberrations, infiltration of immune and stromal cells in proportions correlated with tumor stage and tissue of origin, and evolution between properties previously associated with discrete subtypes. Significance: This study infers whether transcriptome-based groupings of tumors differentiate early in carcinogenesis and are, therefore, appropriate targets for therapy and demonstrates that this is not the case for HGSOC.
Role of Erythropoietin in the Late Anemia of Patients with Chronic Myeloid Leukemia Treated Frontline with Imatinib
Authors: Laura Cesini, Camilla Frieri, Claudia Baratè, Federica Sorà, Marco Cerrano, Antonia Cagnetta, Lara Aprile, Nicola Sgherza, Malgorzata Monika Trawinska, Antonella Gozzini, Ida Carmosino, Federica Ricci, Monica Bocchia, Micaela Bergamaschi, Chiara Aguzzi, Simona Sica, Sara Galimberti, Massimo Breccia, Fabrizio Pane, Luigiana Luciano, Roberto Latagliata
Journal: Blood (2017)
Selective Mesoaccumbal Pathway Inactivation Affects Motivation but Not Reinforcement-Based Learning in Macaques
Authors: Pascaline Vancraeyenest, John T. Arsenault, Xiaolian Li, Qi Zhu, Kenta Kobayashi, Kaoru Isa, Tadashi Isa, Wim Vanduffel
Journal: Neuron (2020)
Necrolytic Migratory Erythema Associated with a Glucagonoma
Authors: Abhirup Banerjee, Sudeep R Shah
Journal: New England Journal of Medicine (2020)

A 48-year-old man with newly diagnosed diabetes mellitus presented with weight loss and an erythematous rash. Evaluation showed elevated serum glucagon levels and a pancreatic mass. A diagnosis of necrolytic migratory erythema associated with a glucagonoma was made.
Targeting the Microenvironment to Overcome Gemcitabine Resistance in Pancreatic Cancer
Authors: Eileen S. Carpenter, Nina G. Steele, Marina Pasca di Magliano
Journal: Cancer Research (2020)

Abstract Pancreatic cancer is characterized by an extensive and complex microenvironment, and is resistant to both chemotherapy and immune checkpoint blockade. The study by Principe and colleagues in this issue of Cancer Research proposes a combinatorial approach based on targeting the very mechanisms of resistance to gemcitabine, a commonly used chemotherapeutic agent. The authors show that gemcitabine treatment causes profound changes in the pancreatic cancer microenvironment, including elevated TGFβ signaling and immune checkpoint expression, as well as increased antigen presentation in tumor cells. Accordingly, they show that the combination of chemotherapy, TGFβ signaling inhibition, and immune checkpoint blockade effectively restores antitumor immunity and results in a significant survival benefit. See related article by Principe et al., p. 3101
Coopetition: cooperation among competitors to enhance applied research and drive innovation in elite sport
Authors: Carlos Ramírez-López, Kevin Till, Andy Boyd, Mark Bennet, Julien Piscione, Sam Bradley, Pierosario Giuliano, Cedric Leduc, Ben Jones
Journal: British Journal of Sports Medicine (2020)

The essence of competition is often understood as a situation of mutually exclusive goal attainment, where one side succeeds only if another does not. However, and as studied by the game theory, this standard view may be too narrow and simplistic when trying to understand complex interactions.1 Researchers in business and management have expanded on this and explored cases of simultaneous cooperation and competition (ie, coopetition) as the most complex but advantageous relationship among competitors and as an effective strategy to drive innovation.2

Scientific innovation can be crucial for maximising athletes’ health and performance, which has resulted in a growing interest in sports science and medicine (SSM). Innovation through research helps develop training models, medical treatments and recovery methods3 but the practical relevance of some fundamental studies is often hindered by their poor ecological validity. Tightly controlled conditions can create an artificial sample of athletes and circumstances which are not truly representative of daily practice, allowing for the gap between research and practice to persist. Applied research aims to bridge that gap by developing ecologically valid evidence and can be further enhanced by embedding ‘off-field’ …
Practical considerations for spirometry during the COVID-19 outbreak: Literature review and insights
Authors: Claudia Crimi, Pietro Impellizzeri, Raffaele Campisi, Santi Nolasco, Antonio Spanevello, Nunzio Crimi
Journal: Pulmonology (2020)

As the Coronavirus disease 2019 (COVID-19) is spreading worldwide, countries are dealing with different phases of the pandemic. Lately, scientific evidence has been growing about the measures for reopening respiratory outpatient services during the COVID-19 pandemic. We aim to summarize the key differences and similarities among recommendations by different national and international organizations.
Cost‐effectiveness of dapagliflozin as a treatment for heart failure with reduced ejection fraction: a multinational health‐economic analysis of <scp>DAPA‐HF</scp>
Authors: Phil McEwan, Oliver Darlington, John J.V. McMurray, Pardeep S. Jhund, Kieran F. Docherty, Michael Böhm, Mark C. Petrie, Klas Bergenheim, Lei Qin
Journal: European Journal of Heart Failure (2020)

Abstract Aim To estimate the cost‐effectiveness of dapagliflozin added to standard therapy, vs. standard therapy only, in patients with heart failure (HF) with reduced ejection fraction (HFrEF), from the perspective of UK, German, and Spanish payers. Methods and results A lifetime Markov model was built to estimate outcomes in patients with HFrEF. Health states were defined by Kansas City Cardiomyopathy Questionnaire total symptom score, type 2 diabetes and worsening HF events. The incidence of worsening HF and all‐cause mortality was estimated using negative binomial regression models and parametric survival analysis, respectively. Direct healthcare costs (2019 British pounds/Euro) and patient‐reported outcomes (EQ‐5D) were sourced from the existing literature and the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF), respectively; the median duration of follow‐up in DAPA‐HF was 18.2 months (range: 0–27.8). Future costs and effects were discounted at 3.0% for the Spanish and German analyses and 3.5% for the UK analysis. In the UK setting, treatment with dapagliflozin was estimated to increase life‐years and quality‐adjusted life‐years (QALYs) from 5.62 to 6.20 (+0.58) and 4.13 to 4.61 (+0.48), respectively, and reduce lifetime hospitalizations for HF (925 and 820 events per 1000 patients for placebo and dapagliflozin, respectively). Similar results were obtained for Germany and Spain. The incremental cost‐effectiveness ratios were £5822, €5379 and €9406/QALY in the UK, Germany and Spain, respectively. In probabilistic sensitivity analyses, more than 90% of simulations were cost‐effective at a willingness‐to‐pay threshold of £20 000/QALY in UK and €20 000/QALY in Germany and Spain. Conclusion Dapagliflozin is likely to be a cost‐effective treatment for HFrEF in the UK, German and Spanish healthcare systems.
Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons
Authors: Radhe Mohan, Amy Y Liu, Paul D Brown, Anita Mahajan, Jeffrey Dinh, Caroline Chung, Sarah McAvoy, Mary Frances McAleer, Steven H Lin, Jing Li, Amol J Ghia, Cong Zhu, Erik P Sulman, John F de Groot, Amy B Heimberger, Susan L McGovern, Clemens Grassberger, Helen Shih, Susannah Ellsworth, David R Grosshans
Journal: Neuro-Oncology (2020)

We investigated differences in radiation-induced grade 3+ lymphopenia (G3+L), defined as an absolute lymphocyte count (ALC) nadir of <500 cells/µL, after proton therapy (PT) or X-ray (photon) therapy (XRT) for patients with glioblastoma (GBM).