tbuckley/cabot-search huggingface dataset:
Selective Targeting of Alternative Splicing Deregulation in Pediatric Acute Myeloid Stem and Progenitor Cells
Authors: Inge Van Der Werf, Phoebe Mondala, Raymond Diep, Larissa Balaian, Cayla Mason, Jacqueline Cloos, Gertjan J.L. Kaspers, Jim La Clair, Peggy Wentworth, Leslie A Crews, Thomas Whisenant, Kathleen Fisch, Michael Burkart, Catriona Jamieson
Journal: Blood (2020)
Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients with Steroid-Refractory/Steroid-Dependent Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study
Authors: Robert Zeiser, Nicola Polverelli, Ron Ram, Shahrukh K. Hashmi, Ronjon Chakraverty, Mary E. D. Flowers, Fitzroy Dawkins, Norbert Hollaender, Maanasa Gowda, Tommaso Stefanelli, Stephanie J. Lee, Takanori Teshima, Franco Locatelli
Journal: Blood (2020)
Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic Analysis of the Cerebrospinal Fluid in Pediatric Leukemia Patients
Authors: Ahmed Hamed Salem, Mohamed A Badawi, Andrew E. Place, Tammy L. Palenski, Richard Arrendale, Su Young Kim, Sara Federico, Todd M. Cooper, Rajeev Menon
Journal: Blood (2020)
Phase 1 Multiple Ascending Dose Study of Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Mitapivat (AG-348) in Subjects with Sickle Cell Disease
Authors: Julia Z. Xu, Anna Conrey, Ingrid Frey, James Nichols, Laurel A Menapace, Laxminath Tumburu, Timothy Lequang, Quan Li, Emily Dunkelberger, Eric Henry, Troy Cellmer, Varsha Iyer, Heidi Mangus, Charles Kung, Lenny Dang, Penelope A. Kosinski, Peter Hawkins, Neal Jeffries, William Eaton, Swee Lay Thein
Journal: Blood (2020)
Abstract 435: P53 Temporally Regulates the Myofibroblast Activation Response in Pressure Overload
Authors: Ryan M Burke, Janet Lighthouse, Pearl J Quijada, Ronald Dirkx, Eric M Small
Journal: Circulation Research (2020)

Heart disease is invariably accompanied by the accumulation of resident cardiac fibroblasts (CF) that secrete extracellular matrix and drive the progression of fibrosis and cardiac dysfunction in heart failure. We recently reported that CF exhibit a unique transcriptional response in physiological and pathological remodeling that may underlie the cardioprotective benefits of exercise, and that p53 targets represent the most dysregulated family between the two. To further investigate the role of p53 in pathological cardiac remodeling, we deleted floxed p53 alleles in adult CF using the tamoxifen-inducible Tcf21 MerCreMer mouse (p53-CFKO). p53-CFKO mice initially retain normal cardiac function through 14 days of pressure overload, but eventually progress to heart failure more rapidly than do p53-CFWT, which show gradual functional decline throughout. CF accumulation and fibrosis at these time points match the functional results closely, with p53-CFKO mice protected from both at 14 days relative to p53-CFWT. Conversely, deletion of p53 in myofibroblasts (MF) using the tamoxifen-inducible Postn MerCreMer mouse (p53-MFKO) resulted in no delay in functional loss nor in CF accumulation and fibrosis, suggesting a distinct temporal window of p53 activity in CF exists in pressure overload. In vitro experimentation confirmed that adenovirally-mediated deletion of p53 could delay, but not reverse, myofibroblast activation - and that this irreversible activation is due to induction of Cdkn2a -mediated cell cycle arrest. Furthermore, unbiased single-cell transcriptomic analysis of CF from pressure-overloaded Tcf21 MerCreMer mice at the 14-day functional inflection point revealed p53-CFKO mice have a unique CF cluster defined primarily by a mitotic signature, and this cluster comes at the direct expense of the myofibroblast population. Clusters representing migrating and quiescent CF were unchanged in response to p53. This work describes an inverse correlation of proliferative capacity and myofibroblast activation that indicates p53 exerts master control of the timing of CF accumulation and pathological fibrosis in heart disease.
The Impact of Bridging Therapy Prior to CAR-T Cell Therapy on Clinical Outcomes of Patients with Relapsed Refractory Large B-Cell Lymphoma
Authors: Forat Lutfi, Ankit Kansagra, Moaath Mustafa Ali, Ali Bukhari, Jonathan Siglin, Jingsheng Yan, Santanu Samanta, Noa G. Holtzman, David Gottlieb, Dong Won Kim, Seung-Tae Lee, Mehmet Hakan Kocoglu, Jean A. Yared, Nancy M. Hardy, Jason Molitoris, Pranshu Mohindra, Aaron P. Rapoport, Saurabh Dahiya
Journal: Blood (2020)
PVAG Regimen (Prednisone, Vinblastine, Doxorubicin, Gemcitabine) Used in Real-Life Setting in First Line Therapy for Elderly Classical Hodgkin Lymphoma Patients: A Retrospective Study of Lysa Centers
Authors: Guillaume Aussedat, Maryam Idlhaj, Amandine Durand, Xavier Roussel, Pauline Brice, Gilles Salles, Benedicte Deau Fischer, Adrien Chauchet, Cedric Rossi, Herve Ghesquieres
Journal: Blood (2020)
Graphene oxide improves postoperative cognitive dysfunction by maximally alleviating amyloid beta burden in mice
Authors: Jiqian Zhang, Shasha Zhu, Peipei Jin, Yuting Huang, Qingqing Dai, Qianyun Zhu, Pengfei Wei, Zhilai Yang, Lei Zhang, Hu Liu, Guanghong Xu, Lijian Chen, Erwei Gu, Yunjiao Zhang, Longping Wen, Xuesheng Liu
Journal: Theranostics (2020)

Rationale: Graphene oxide (GO) based nanomaterials have shown potential for the diagnosis and treatment of amyloid-β (Aβ)-related diseases, mainly on Alzheimer's disease (AD). However, these nanomaterials have limitations. How GO is beneficial to eliminate Aβ burden, and its physiological function in Aβ-related diseases, still needs to be investigated. Moreover, postoperative cognitive dysfunction (POCD) is an Aβ-related common central nervous system complication, however, nanomedicine treatment is lacking. Methods: To evaluate the effects of GO on Aβ levels, HEK293T-APP-GFP and SHSY5Y-APP-GFP cells are established. Intramedullary fixation surgery for tibial fractures under inhalation anesthesia is used to induce dysfunction of fear memory in mice. The fear memory of mice is assessed by fear conditioning test. Results: GO treatment maximally alleviated Aβ levels by simultaneously reducing Aβ generation and enhancing its degradation through inhibiting β-cleavage of amyloid precursor protein (APP) and improving endosomal Aβ delivery to lysosomes, respectively. In postoperative mice, the hippocampal Aβ levels were significantly increased and hippocampal-dependent fear memory was impaired. However, GO administration significantly reduced hippocampal Aβ levels and improved the cognitive function of the postoperative mice. Conclusion: GO improves fear memory of postoperative mice by maximally alleviating Aβ accumulation, providing new evidence for the application of GO-based nanomedicines in Aβ-related diseases.
Diffuse Large B Cell Lymphoma Genetic Classification By Targeted Sequencing and Associations with Immunochemotherapy-Treated Patients' Clinical Outcome
Authors: Lucia Pedrosa Perez, Ismael Fernández-Miranda, David Perez Callejo, Cristina Quero, Marta Rodriguez, Paloma Martin-Acosta, Sagrario Gomez, Julia González-Rincón, Adrian Santos, Carlos Tarin, Juan F. Garcia, Francisco R García-Arroyo, Antonio Rueda, Francisca I Camacho, Monica Garcia-Cosio, Ana Heredero, Marta Llanos, Manuela Mollejo, Miguel Piris-Villaespesa, José Gómez Codina, Natalia Yanguas-Casás, Antonio Sánchez, Miguel A. Piris, Mariano Provencio, Margarita Sanchez-Beato
Journal: Blood (2020)
Impact of grouping serial journal articles by disease category: analysis of article placement order in <i>ARD</i> 2013–2019
Authors: Janine Hill, Nicola Dalbeth, Greg D Gamble, Andrew Grey, Sarah Stewart
Journal: Annals of the Rheumatic Diseases (2020)

Article placement order within journal issues has the potential to influence perceived research importance, with earlier listed articles being more visible and more likely to be downloaded and cited.1 2 In an analysis of serial rheumatology journals published between 2013 and 2018, we reported that certain rheumatic diseases were prioritised within journal issues.1 Articles about rheumatoid arthritis were preferentially ordered at the front of issues, while other diseases including connective tissue diseases, crystal arthritis, paediatric syndromes and pain syndromes were consistently ordered towards the back. This prioritisation was evident in journals with disease-specific tables of contents sections within issues, but was not observed in journals that did not group content by disease category.

Prior to 2019, Annals of the Rheumatic Diseases (ARD) did not group articles within each issue by disease category. In the first issue of 2019, ARD announced ‘small but visible structural changes’ in which articles would be grouped within each issue by disease category.3 We set out to determine whether specific rheumatic diseases were prioritised or deprioritised by this change in policy.

We analysed all original research articles published in ARD between June 2013 and December 2019. Each article was coded into one of …
Abstract 340: Myocyte-borne Bdnf is Essential to Limit Post-ischemic Cardiac Injury and Dysfunction
Authors: Seungho Jun, Jacopo Agrimi, Alessandro Cannavo, Gizem Keceli, Christian U Oeing, Alexander Eremiev, Lorenzo Marcucci, Aram Megighian, Giuseppe RENGO, Walter J Koch, Nazareno Paolocci
Journal: Circulation Research (2020)

Brain-derived neurotrophic factor (BDNF)/ tyrosine receptor kinase B (TrkB) signaling is essential for normal cardiac contraction/relaxation. Alterations in this pathway, i.e., defective neuronal BDNF, account for post-ischemic cardiac injury. Less clear, however, is whether myocyte-borne BDNF has a role in this setting. We generated myocyte-selective BDNF knock-out (myoBDNF -/- ) mice, using Myh6-Cre mice crossed with BDNF floxed mice, confirming bdnf deletion via RT-PCR in isolated myocytes. Hearts from 12-wk old myoBDNF -/- mice and WT littermates underwent global ischemia (30 min) and reperfusion (2 h). At this age, the two strains had similar left ventricular (LV) sizes and fractional shortening [63±1.1 (WT) vs. 60±1.2% (myoBDNF -/- )]. At reperfusion, myoBDNF -/- hearts displayed larger infarct size compared to WT (38±3 vs. 14±2%, n=9, p&lt;.0001) and worsened LV functional recovery ( Fig. 1 ). For example, the rate-pressure product recuperated only by 14±1.5 in myoBDNF -/- mice vs. 36±3% in WT (p&lt;.0001). The two groups had similar heart rates at 2 h reperfusion, however myoBDNF -/- mice markedly lost their contractility [dP/dt max = 436±58 vs. 1407±142 mmHg/sec (WT), p&lt; .0001], likely due to the exacerbated myocyte loss. Accordingly, post-ischemic troponin I release was significantly higher in myoBDNF -/- than in WT mice (0.9±0.04 vs. 1.3±0.04 ng/ml, p&lt;.0002). Thus, deleting bdnf in myocytes severely limits recovery after ischemia, directly linking myocyte-borne BDNF to the heart response to injury. Therefore, preserving or enhancing autologous myocyte BDNF generation offers new avenues to counter cardiac ischemic injury and subsequent heart failure progression.
The Scaffolding Protein NEDD9 Regulates Chronic Lymphocytic Leukemia Cell Migration Via the CXCR4 - CXCL12 Axis and Promotes Disease Progression
Authors: Lisa Rusyn, Sebastian Reinartz, Anastasia Nikiforov, Nelly Mikhael, Christian Pallasch, Reinhard Buettner, Michael Hallek, Phuong Hien Nguyen, Tamina Seeger-Nukpezah
Journal: Blood (2020)
Age is in the Eye of the Beholder: Distinguishing Molecular Signatures in Early-onset Pancreatic Adenocarcinomas
Authors: Emil Lou
Journal: Clinical Cancer Research (2020)

Pancreatic ductal adenocarcinoma (PDAC) is more prevalent in older patients, but early-onset cases (<55 years) may be a distinct genetic subpopulation. Differential expression of CDKN2A and transcription factor FOXC2 were found in early-onset cases. This finding opens the door to investigating additional features that distinguish PDAC tumors in this age group.See related article by Tsang et al., p. 246.
Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis
Authors: Andrew Charles Perkins, Kate Burbury, Thomas Lehmann, David M Ross, Andreas Reiter, Vikas Gupta, Claire Harrison, Jean-Jacques Kiladjian, Alessandro M. Vannucchi, Marielle Wondergem, Robert Pack, Monika Wroclawska, Celine Wilke, Angela Zhang, Florian H. Heidel
Journal: Blood (2020)
AB0015 MICRORNA-155 EXPRESSION IN BEHÇET’S DISEASE
Authors: Aida Saleh, Abeer Elhadidi, Abeer Abdelati, Nadeen Saad
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Mature microRNAs (miRNAs) are a class of naturally occurring, small non-coding RNA molecules. MicroRNAs are partially complementary to one or more messenger RNA (mRNA) molecules, and their main function is to downregulate gene expression in a variety of manners, including translational repression, mRNA cleavage, and deadenylation. Recent miRNA deletion studies have revealed a central role in the regulation of the immune response. The deletion of miRNA-155 impairs T and B cell differentiation in germinal centers, and greatly affects antibodies and cytokines production. Furthermore, aberrant expression of miR-155 has been reported in human autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus.[1] Whether miR-155 plays a role in the pathogenesis of Behçet's Disease is not yet known and is therefore the subject of this study. <h3>Objectives</h3> The aim of this work is to study the expression of microRNA-155 as a molecular biomarker in Behcet's disease. <h3>Methods</h3> Thirty patients with Behçet's disease and 15 healthy matched controls were included. Patients fulfilled the International Study Group (ISG) diagnostic Criteria of Behçet's Disease. Exclusion Criteria included other types of primary or secondary vasculitis; reactive arthritis; inflammatory bowel disease; current or past history of cancer, chemotherapy or radiotherapy; current infection; long standing diabetes mellitus; and hypertension. Total RNA, including miRNAs isolation, from peripheral blood mononuclear cells (PBMCs) was extracted by using miRNeasy Mini Kit (QIAGEN, cat. no. 217004). This was followed by reverse transcription into complementery DNA (cDNA). Expression of microRNA-155 was carried out using quantitative real time polymerase chain reaction (RQ_PCR). Relative expression of microRNA155 was calculated using 2 - ΔΔ <sup>ct</sup> formula. Where ct = (ct miRNA – ct miRNA control) and Ct is the fractional cycle number at which the fluorescence passes the fixed threshold. <h3>Results</h3> Our results showed a significantly decreased expression of miR-155 in peripheral blood mononuclear cells (PBMCs) of Behçet's disease patients with active disease compared to that in patients with inactive disease as well as healthy control (p=0.026). The level of miR-155 showed a significant positive correlation with patients' age (p=0.042), and significant negative correlation with BDCAF activity score of the disease (p=0.034), and platelets count (p=0.011) (Table1). <h3>Conclusion</h3> Downregulation of miR-155 expression in active BD patients may be used as a molecular biomarker for increasing activity and severity of Behcet's disease. This pathway could be a potential target for a new therapeutic strategy. <h3>References</h3> [1] Kurowska-Stolarska M, Alivernini S, Ballantine LE, et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci2011;108: 11193–8. <h3>Disclosure of Interests</h3> None declared
DNA Methylation-Mediated Silencing of Mir-204 Enhances the Occurrence of T-Cell Acute Lymphoblastic Leukemia By Upregulating MMP-2 and MMP-9 through the NF-Κb Signaling Pathway
Authors: Dabing Chen, Tingting Xiao, Dandan Lin, Haojie Zhu, Jingjing Xu, Xiaofeng Luo, Jinhua Ren, Zhihong Zheng, Zhizhe Chen, Jianda Hu, Ting Yang
Journal: Blood (2020)
Ticagrelor or Prasugrel in Patients With ST-Segment–Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Alp Aytekin, Gjin Ndrepepa, Franz-Josef Neumann, Maurizio Menichelli, Katharina Mayer, Jochen Wöhrle, Isabell Bernlochner, Shqipdona Lahu, Gert Richardt, Bernhard Witzenbichler, Dirk Sibbing, Salvatore Cassese, Dominick J. Angiolillo, Christian Valina, Sebastian Kufner, Christoph Liebetrau, Christian W. Hamm, Erion Xhepa, Alexander Hapfelmeier, Hendrik B. Sager, Isabel Wustrow, Michael Joner, Dietmar Trenk, Massimiliano Fusaro, Karl-Ludwig Laugwitz, Heribert Schunkert, Stefanie Schüpke, Adnan Kastrati
Journal: Circulation (2020)

Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention.In this prespecified subgroup analysis, we included 1653 patients with ST-segment-elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization.The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95-1.82]; P=0.10). One-year incidence of all-cause death (4.9% versus 4.7%; P=0.83), stroke (1.3% versus 1.0%; P=0.46), and definite stent thrombosis (1.8% versus 1.0%; P=0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18-3.23]; P=0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80-1.87]; P=0.36).In patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01944800.
Sustainable health equity: achieving a net-zero UK
Authors: Alice Munro, Tammy Boyce, Michael Marmot
Journal: The Lancet Planetary Health (2020)

Tony Atkinson's 2015 book Inequality begins with the observation that, according to population surveys in the USA and Europe, the two biggest global problems are inequality and climate change.1 These two big problems need to be tackled at the same time. In particular, combatting climate change and reducing avoidable health inequalities—promoting health equity—should be part of a common agenda. We label it sustainable health equity.
Multisystem Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Treatment of Non–Small Cell Lung Cancer
Authors: Bairavi Shankar, Jiajia Zhang, Abdul Rafeh Naqash, Patrick M. Forde, Josephine L. Feliciano, Kristen A. Marrone, David S. Ettinger, Christine L. Hann, Julie R. Brahmer, Biagio Ricciuti, Dwight Owen, Yukihiro Toi, Paul Walker, Gregory A. Otterson, Sandip H. Patel, Shunichi Sugawara, Jarushka Naidoo
Journal: JAMA Oncology (2020)

The spectrum of individual immune-related adverse events (irAEs) from anti-programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) has been reported widely, and their development is associated with improved patient survival across tumor types. The spectrum and impact on survival for patients with non-small cell lung cancer (NSCLC) who develop multisystem irAEs from ICIs, has not been described.To characterize multisystem irAEs, their association with survival, and risk factors for multisystem irAE development.This retrospective cohort study carried out in 5 academic institutions worldwide included 623 patients with stage III/IV NSCLC, treated with anti-PD-(L)1 ICIs alone or in combination with another anticancer agent between January 2007 and January 2019.Anti-PD-(L)1 monotherapy or combinations.Multisystem irAEs were characterized by combinations of individual irAEs or organ system involved, separated by ICI-monotherapy or combinations. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Differences in PFS and OS between irAE groups were assessed by multivariable models. Risk for multisystem irAE was estimated as odds ratios by multivariable logistic regression.The 623 patients included in the study were mostly men (60%, n = 375) and White (77%, n = 480). The median (range) age was 66 (58-73) years, and 148 patients (24%) developed a single irAE, whereas 58 (9.3%) developed multisystem irAEs. The most common multisystem irAE patterns in patients receiving anti-PD-(L)1 monotherapy were pneumonitis thyroiditis (n = 7, 14%), hepatitis thyroiditis (n = 5, 10%), dermatitis pneumonitis (n = 5, 10%), and dermatitis thyroiditis (n = 4, 8%). Favorable Eastern Cooperative Oncology Group (ECOG) performance status (PS) (ECOG PS = 0/1 vs 2; adjusted odds ratio [aOR], 0.27; 95% CI, 0.08-0.94; P = .04) and longer ICI duration (aOR, 1.02; 95% CI, 1.01-1.03; P < .001) were independent risk factors for development of multisystem irAEs. Patients with 1 irAE and multisystem irAEs demonstrated incrementally improved OS (adjusted hazard ratios [aHRs], 0.86; 95% CI, 0.66-1.12; P = .26; and aHR, 0.57; 95% CI, 0.38-0.85; P = . 005, respectively) and PFS (aHR, 0.68; 95% CI, 0.55-0.85; P = .001; and aHR, 0.39; 95% CI, 0.28-0.55; P < .001, respectively) vs patients with no irAEs, in multivariable models adjusting for ICI duration.In this multicenter cohort study, development of multisystem irAEs was associated with improved survival in patients with advanced NSCLC treated with ICIs.