tbuckley/cabot-search huggingface dataset:
Improved Titer and Gene Transfer by Lentiviral Vectors Using Novel, Small β-Globin Locus Control Region Elements
Authors: Richard A. Morgan, Mildred J. Unti, Bamidele Aleshe, Devin Brown, Kyle S. Osborne, Colin Koziol, Paul G. Ayoub, Oliver B. Smith, Rachel O’Brien, Curtis Tam, Eric Miyahira, Marlene Ruiz, Jason P. Quintos, Shantha Senadheera, Roger P. Hollis, Donald B. Kohn
Journal: Molecular Therapy (2019)

β-globin lentiviral vectors (β-LV) have faced challenges in clinical translation for gene therapy of sickle cell disease (SCD) due to low titer and sub-optimal gene transfer to hematopoietic stem and progenitor cells (HSPCs). To overcome the challenge of preserving efficacious expression while increasing vector performance, we used published genomic and epigenomic data available through ENCODE to redefine enhancer element boundaries of the β-globin locus control region (LCR) to construct novel ENCODE core sequences. These novel LCR elements were used to design a β-LV of reduced proviral length, termed CoreGA-AS3-FB, produced at higher titers and possessing superior gene transfer to HSPCs when compared to the full-length parental β-LV at equal MOI. At low vector copy number, vectors containing the ENCODE core sequences were capable of reversing the sickle phenotype in a mouse model of SCD. These studies provide a β-LV that will be beneficial for gene therapy of SCD by significantly reducing the cost of vector production and extending the vector supply. β-globin lentiviral vectors (β-LV) have faced challenges in clinical translation for gene therapy of sickle cell disease (SCD) due to low titer and sub-optimal gene transfer to hematopoietic stem and progenitor cells (HSPCs). To overcome the challenge of preserving efficacious expression while increasing vector performance, we used published genomic and epigenomic data available through ENCODE to redefine enhancer element boundaries of the β-globin locus control region (LCR) to construct novel ENCODE core sequences. These novel LCR elements were used to design a β-LV of reduced proviral length, termed CoreGA-AS3-FB, produced at higher titers and possessing superior gene transfer to HSPCs when compared to the full-length parental β-LV at equal MOI. At low vector copy number, vectors containing the ENCODE core sequences were capable of reversing the sickle phenotype in a mouse model of SCD. These studies provide a β-LV that will be beneficial for gene therapy of SCD by significantly reducing the cost of vector production and extending the vector supply.
Unlocking the Secrets of Mitochondria in the Cardiovascular System
Authors: Rong Tian, Wilson S. Colucci, Zoltan Arany, Markus M. Bachschmid, Scott W. Ballinger, Sihem Boudina, James E. Bruce, David W. Busija, Sergey Dikalov, Gerald W. Dorn, Zorina S. Galis, Roberta A. Gottlieb, Daniel P. Kelly, Richard N. Kitsis, Mark J. Kohr, Daniel Levy, E. Douglas Lewandowski, Joseph M. McClung, Daria Mochly-Rosen, Kevin D. O’Brien, Brian O’Rourke, Joon-Young Park, Peipei Ping, Michael N. Sack, Shey-Shing Sheu, Yang Shi, Sruti Shiva, Douglas C. Wallace, Robert G. Weiss, Hilary J. Vernon, Renee Wong, Lisa Schwartz Longacre, Scarlet Shi
Journal: Circulation (2019)

Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure, and other cardiovascular diseases, as well, but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute convened a group of leading experts in heart failure, cardiovascular diseases, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational, and clinical research focusing on the potential of mitochondria-based therapeutic strategies in heart failure. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of heart failure and cardiovascular diseases by using mitochondria-based approaches.
Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior
Authors: Mark A. Smith, Agharul I. Choudhury, Justyna A. Glegola, Paulius Viskaitis, Elaine E. Irvine, Pedro Caldas Custodio de Campos Silva, Sanjay Khadayate, Hanns Ulrich Zeilhofer, Dominic J. Withers
Journal: Journal of Clinical Investigation (2019)

Arcuate nucleus agouti–related peptide (AgRP) neurons play a central role in feeding and are under complex regulation by both homeostatic hormonal and nutrient signals and hypothalamic neuronal pathways. Feeding may also be influenced by environmental cues, sensory inputs, and other behaviors, implying the involvement of higher brain regions. However, whether such pathways modulate feeding through direct synaptic control of AgRP neuron activity is unknown. Here, we show that nociceptin-expressing neurons in the anterior bed nuclei of the stria terminalis (aBNST) make direct GABAergic inputs onto AgRP neurons. We found that activation of these neurons inhibited AgRP neurons and feeding. The activity of these neurons increased upon food availability, and their ablation resulted in obesity. Furthermore, these neurons received afferent inputs from a range of upstream brain regions as well as hypothalamic nuclei. Therefore, aBNST GABAergic nociceptin neurons may act as a gateway to feeding behavior by connecting AgRP neurons to both homeostatic and nonhomeostatic neuronal inputs.
Stable Engraftment with Haploidentical Peripheral Blood Stem Cell Transplantation in Adult Patients with Sickle Cell Disease
Authors: Santosh L. Saraf, Pritesh Patel, Karen Sweiss, Oh Annie, Matthew Koshy, Sally Campbell-lee, Michel Gowhari, Shivi Jain, David Peace, John G. Quigley, Irum Khan, Robert E. Molokie, Nadim Mahmud, Victor R. Gordeuk, Damiano Rondelli
Journal: Blood (2017)
Medical device surveillance with electronic health records
Authors: Alison Callahan, Jason A. Fries, Christopher Ré, James I. Huddleston, Nicholas J. Giori, Scott Delp, Nigam H. Shah
Journal: npj Digital Medicine (2019)

Abstract Post-market medical device surveillance is a challenge facing manufacturers, regulatory agencies, and health care providers. Electronic health records are valuable sources of real-world evidence for assessing device safety and tracking device-related patient outcomes over time. However, distilling this evidence remains challenging, as information is fractured across clinical notes and structured records. Modern machine learning methods for machine reading promise to unlock increasingly complex information from text, but face barriers due to their reliance on large and expensive hand-labeled training sets. To address these challenges, we developed and validated state-of-the-art deep learning methods that identify patient outcomes from clinical notes without requiring hand-labeled training data. Using hip replacements—one of the most common implantable devices—as a test case, our methods accurately extracted implant details and reports of complications and pain from electronic health records with up to 96.3% precision, 98.5% recall, and 97.4% F1, improved classification performance by 12.8–53.9% over rule-based methods, and detected over six times as many complication events compared to using structured data alone. Using these additional events to assess complication-free survivorship of different implant systems, we found significant variation between implants, including for risk of revision surgery, which could not be detected using coded data alone. Patients with revision surgeries had more hip pain mentions in the post-hip replacement, pre-revision period compared to patients with no evidence of revision surgery (mean hip pain mentions 4.97 vs. 3.23; t = 5.14; p &lt; 0.001). Some implant models were associated with higher or lower rates of hip pain mentions. Our methods complement existing surveillance mechanisms by requiring orders of magnitude less hand-labeled training data, offering a scalable solution for national medical device surveillance using electronic health records.
Is rituximab (R) the optimal therapeutic intervention (TI) for post-transplant lymphoproliferative disorder (PTLD) following solid organ transplant (SOT)?
Authors: R. E. Tsao, T. Jin, B. Richendollar, E. Hsi, B. Pohlman
Journal: Journal of Clinical Oncology (2007)

8074 Background: PTLD is a rare, often fatal, complication of SOT. Most are derived from CD20+ B-cells. Historically, patients (pts) received a variety of TIs ranging from decreased immunosuppression to chemotherapy (CT). Based on promising initial study results, most pts now receive rituximab (R) without CT as part of 1 st TI. Methods: We searched the Cleveland Clinic pathology archives for SOT pts, who were diagnosed with PTLD between 1987 and 2006; reviewed the medical records; extracted clinical information and outcomes; and analyzed the data by Cox proportional univariate and multivariate analyses. Results: We identified 55 SOT pts (heart, 18; lung, 16; kidney 14; liver, 6; pancreas, 1), who were diagnosed with PTLD at median age 47 years (range 7–66). The median time from SOT to PTLD was 1.7 years (range .2–20.9). 1 st TI (usually &gt;1) included “complete” resection (4), decreased immunosuppresion (53), acyclovir or ganciclovir (28), interferon (4), radiation therapy (6), CT (12), and/or R (17). Response to 1 st TI was CR (30) or PR (10). The median follow-up among surviving pts is 5.0 years (range .1–11.4). 29 (including 5 CT and 5 R) pts have died; only 2 CT but all 5 R pts died from PTLD. On univariate analysis, younger age + , &lt;2 prior rejection episodes + *, PS &lt;2 + *, normal LDH + *, &lt;2 extranodal sites + , lower IPI + *, &gt;1 1 st TI + , and 1 st TI with CT* were associated with an improved overall survival (OS) + and/or PTLD-specific survival (PSS)*. On multivariate analysis, only PS &lt;2 (HR 0.04 [CI 0.01–0.14], p&lt;0.001) and &gt;1 1 st TI (HR 0.43 [CI 0.19–0.97], p=0.041) were associated with improved OS while PS &lt;2 (HR 0.04 [0.01- 0.16], p&lt;0.001) and 1 st TI with CT (HR 0.19 [CI 0.04–0.84], p&lt;0.028) were associated with improved PSS. Conclusions: A significant minority of SOT pts that receive R without CT as part of 1 st TI still die from PTLD. PS is the most important predictor of outcome. In conjunction with the improved survival observed in de novo B-cell NHL pts treated with R+CT (compared to CT alone), this retrospective analysis suggests that some SOT PTLD pts should receive R+CT as part of 1 st TI. No significant financial relationships to disclose.
TCT-337 Outcomes of Heart Failure With Reduced Ejection Fraction Status Post Implantable Cardioverter-Defibrillator Presenting with HFrEF Exacerbation With Versus Without Atrial Fibrillation
Authors: Hassaan Arshad, Sara Butt, Mirela Feurdean, Pallavi Solanki
Journal: Journal of the American College of Cardiology (2019)
Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease
Authors: Gregg W. Stone, A. Pieter Kappetein, Joseph F. Sabik, Stuart J. Pocock, Marie-Claude Morice, John Puskas, David E. Kandzari, Dimitri Karmpaliotis, W. Morris Brown, Nicholas J. Lembo, Adrian Banning, Béla Merkely, Ferenc Horkay, Piet W. Boonstra, Ad J. van Boven, Imre Ungi, Gabor Bogáts, Samer Mansour, Nicolas Noiseux, Manel Sabaté, Jose Pomar, Mark Hickey, Anthony Gershlick, Pawel E. Buszman, Andrzej Bochenek, Erick Schampaert, Pierre Pagé, Rodrigo Modolo, John Gregson, Charles A. Simonton, Roxana Mehran, Ioanna Kosmidou, Philippe Généreux, Aaron Crowley, Ovidiu Dressler, Patrick W. Serruys
Journal: New England Journal of Medicine (2019)

Long-term outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents, as compared with coronary-artery bypass grafting (CABG), in patients with left main coronary artery disease are not clearly established.
Respiratory physiotherapy in the bronchiectasis guidelines: is there a loud voice we are yet to hear?
Authors: Arietta Spinou, James D. Chalmers
Journal: European Respiratory Journal (2019)

Bronchiectasis is a chronic respiratory disease of airway dilatation, where patients typically suffer from respiratory infections, fatigue, sputum, cough, dyspnoea and poor quality of life [1, 2]. This condition has received increased interest over the past years, with important developments in establishing national and international patient registries [3–5], randomised controlled trials of new treatments [6–8] and disease-specific health status questionnaires, such as the Bronchiectasis Health Questionnaire and the Quality of Life Questionnaire – Bronchiectasis [9, 10]. A number of new treatment approaches have been proposed including long term antibiotic therapies and immune modulating drugs [6, 7, 11, 12]. A call for action for great awareness and research into airway clearance techniques and pulmonary rehabilitation in bronchiectasis <http://bit.ly/2L8F4Va>
TCT-317 Impact of Coronary Artery Dominance on Prognosis After PCI and CABG for Unprotected Left Main Disease: Analysis From the EXCEL Trial
Authors: Eisuke Usui, Akiko Maehara, Masahiko Noguchi, Tatsuhiro Fujimura, Fotios Gkargkoulas, Ziad Ali, Yiran Zhang, A. Pieter Kappetein, Joseph Sabik, Patrick Serruys, Gary Mintz, Philippe Genereux, Gregg Stone
Journal: Journal of the American College of Cardiology (2019)
TCT-710 Body Mass Index as a Predictor of Outcomes in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Majid Asawaeer, Rahul Dhawan, Andrew Goldsweig, Yiannis Chatzizisis, Poonam Velagapudi, Edward O’Leary, Gregory Pavlides, David Barton
Journal: Journal of the American College of Cardiology (2019)
Emergent high fatality lung disease in systemic juvenile arthritis
Authors: Vivian E Saper, Guangbo Chen, Gail H Deutsch, R Paul Guillerman, Johannes Birgmeier, Karthik Jagadeesh, Scott Canna, Grant Schulert, Robin Deterding, Jianpeng Xu, Ann N Leung, Layla Bouzoubaa, Khalid Abulaban, Kevin Baszis, Edward M Behrens, James Birmingham, Alicia Casey, Michal Cidon, Randy Q Cron, Aliva De, Fabrizio De Benedetti, Ian Ferguson, Martha P Fishman, Steven I Goodman, T Brent Graham, Alexei A Grom, Kathleen Haines, Melissa Hazen, Lauren A Henderson, Assunta Ho, Maria Ibarra, Christi J Inman, Rita Jerath, Khulood Khawaja, Daniel J Kingsbury, Marisa Klein-Gitelman, Khanh Lai, Sivia Lapidus, Clara Lin, Jenny Lin, Deborah R Liptzin, Diana Milojevic, Joy Mombourquette, Karen Onel, Seza Ozen, Maria Perez, Kathryn Phillippi, Sampath Prahalad, Suhas Radhakrishna, Adam Reinhardt, Mona Riskalla, Natalie Rosenwasser, Johannes Roth, Rayfel Schneider, Dieneke Schonenberg-Meinema, Susan Shenoi, Judith A Smith, Hafize Emine Sönmez, Matthew L Stoll, Christopher Towe, Sara O Vargas, Richard K Vehe, Lisa R Young, Jacqueline Yang, Tushar Desai, Raymond Balise, Ying Lu, Lu Tian, Gill Bejerano, Mark M Davis, Purvesh Khatri, Elizabeth D Mellins
Journal: Annals of the Rheumatic Diseases (2019)

To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.
Identification of a Novel BCR-ABL1 Fusion Transcript in a Chronic Myeloid Leukemia (CML) Patient By Unique Molecular Methods and Subsequent Monitoring of the Patient's Response to Tyrosine Kinase Inhibitor (TKI) Therapy
Authors: Durga Prasad Dash, Valerie Trap-stamborski, Curt Czajkowski, Daniel Rauscher, Raju Pillai
Journal: Blood (2018)
TCT-555 The Association of Health-Related Quality-of-Life Scores With Cardiovascular and Limb Outcomes in Patients With Symptomatic Peripheral Artery Disease: Insights From the EUCLID Trial
Authors: Jennifer Rymer, Hillary Mulder, Kim Smolderen, William Hiatt, Michael Conte, Jeffrey Berger, Brian Katona, Lars Norgren, Kenneth Mahaffey, Frank Rockhold, F. Gerry Fowkes, Schuyler Jones, Manesh Patel
Journal: Journal of the American College of Cardiology (2019)
High-Intensity Versus Low-Intensity Surveillance for Patients With Colorectal Adenomas
Authors: Reinier G.S. Meester, Iris Lansdorp-Vogelaar, Sidney J. Winawer, Ann G. Zauber, Amy B. Knudsen, Uri Ladabaum
Journal: Annals of Internal Medicine (2019)

Surveillance of patients with colorectal adenomas has limited long-term evidence to support current practice.To compare the lifetime benefits and costs of high- versus low-intensity surveillance.Microsimulation model.U.S. cancer registry, cost data, and published literature.U.S. patients aged 50, 60, or 70 years with low-risk adenomas (LRAs) (1 to 2 small adenomas) or high-risk adenomas (HRAs) (3 to 10 small adenomas or ≥1 large adenoma) removed after screening with colonoscopy or fecal immunochemical testing (FIT).Lifetime.Societal.No further screening or surveillance, routine screening after 10 years, low-intensity surveillance (10 years after LRA removal and 5 years after HRA removal), and high-intensity surveillance (5 years after LRA removal and 3 years after HRA removal).Colorectal cancer (CRC) incidence and incremental cost-effectiveness.Without surveillance or screening, lifetime CRC incidence for patients aged 50 years was 10.9% after LRA removal and 17.2% after HRA removal at screening colonoscopy. Subsequent colonoscopic screening, low-intensity surveillance, or high-intensity surveillance decreased incidence by 39%, 46% to 48%, and 55% to 56%, respectively. Incidence of CRC and surveillance benefits were higher for adenomas detected at FIT screening and lower for older patients. High-intensity surveillance cost less than $30 000 per quality-adjusted life-year (QALY) gained compared with low-intensity surveillance.High-intensity surveillance cost less than $100 000 per QALY gained in most alternative scenarios for adenoma recurrence, CRC incidence, longevity, quality of life, screening ages, surveillance ages, test performance, disutilities, and cost.Few surveillance outcome data exist.The model suggests that high-intensity surveillance as recommended in the United States provides modest but clinically relevant benefits over low-intensity surveillance at acceptable cost.National Cancer Institute.
TCT-756 Incidence of Patient Prosthesis Mismatch Following Native and Valve-in-Valve Transcatheter Aortic Valve Replacement Based on Indexed Aortic Valve Area Compared to Energy Loss Index
Authors: Ramy Mando, George Hanzel, Michael Gallagher, Robert Safian, Safwan Kassas, Francis Shannon, Amr Abbas
Journal: Journal of the American College of Cardiology (2019)
Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma
Authors: Takashi Sato, Seungyeul Yoo, Ranran Kong, Abhilasha Sinha, Prashanth Chandramani-Shivalingappa, Ayushi Patel, Maya Fridrikh, Osamu Nagano, Takashi Masuko, Mary Beth Beasley, Charles A. Powell, Jun Zhu, Hideo Watanabe
Journal: Cancer Research (2019)

Abstract Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed “neural” subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein–protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the “neural” LUSC. Forced expression of p63 downregulated Brn2 in the “neural” LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK–ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted. Significance: Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.
TCT-548 Clinical and Angiographic Lesion Characteristics Associated With Lack of Angina Relief After PCI: Insights From the RIVER-PCI Trial
Authors: Akiko Fujino, Akiko Maehara, Giora Weisz, Philippe Généreux, Aaron Crowley, Gary Mintz, Ovidiu Dressler, Stefan James, Ori Ben-Yehuda, E. Magnus Ohman, Gregg Stone
Journal: Journal of the American College of Cardiology (2019)
TCT-468 Clinical Features, Sex Differences, and Outcomes of Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA): A Multicenter, International, Registry Analysis
Authors: Richard Jung, Simon Parlow, Trevor Simard, Christopher Chen, Harshpreet Ghataura, Aditya Kishore, Aravinda Perera, Robert Moreland, Ian Hughes, Rosanna Tavella, Benjamin Hibbert, John Beltrame, Kuljit Singh
Journal: Journal of the American College of Cardiology (2019)
Minimal Residual Disease By Flow Cytometry in Multiple Myeloma Based on Euro-Flow Panel in Patients with Clinical Remission of the Disease
Authors: Antonio Carrasco-Yalán, John W Pando-Mayta, Tania Soto-Delgado, Eva H Obregon-Zegarra, Jorge J Valdés-Gómez, Marylin Cuyutupac-Barja, Jorge F Castillo-Aguirre, Jose M Guevara-Canales
Journal: Blood (2017)
TCT-355 Serial (Baseline and Follow-Up) Optical Coherence Tomography Analysis of the Causes of Stent Failure
Authors: Mingyou Zhang, Masaru Ishida, Gary Mintz, Mitsuaki Matsumura, Zhaoyang Chen, Ziad Ali, Craig Porter, Jane Cao, Thomas Pappas, Jeffrey W. Moses, Allen Jeremias, Richard Shlofmitz, Akiko Maehara
Journal: Journal of the American College of Cardiology (2019)
TCT-480 Specific Intraprocedural Adverse Events With New-Generation Self-Expandable TAVR Devices: Is It All a Matter of Device Size?
Authors: Verena Veulemans, Katharina Hellhammer, Oliver Maier, Kerstin Piayda, Shazia Afzal, Malte Kelm, Tobias Zeus
Journal: Journal of the American College of Cardiology (2019)
Mass Spectrometry-Based Immunopeptidome Analysis of Acute Myeloid Leukemia Cells Under Decitabine Treatment Delineates Induced Presentation of Cancer/Testis Antigens on HLA Class I Molecules
Authors: Jens Bauer, Nora Zieger, Annika Nelde, Leon Bichmann, Helmut R. Salih, Lothar Kanz, Hans-Georg Rammensee, Stefan Stevanovic, Juliane S. Walz
Journal: Blood (2018)