tbuckley/cabot-search huggingface dataset:
Locating animals with respect to landmarks in space-time
Authors: Hunter Gentry, Cameron Buckner
Journal: Behavioral and Brain Sciences (2019)

Abstract Landmarks play a crucial role in bootstrapping both spatial and temporal cognition. Given the similarity in the underlying demands of representing spatial and temporal relations, we ask here whether animals can be trained to reason about temporal relations by providing them with temporal landmark cues, proposing a line of future research complementary to those suggested by the authors.
CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration
Authors: Christopher L. Nobles, Scott Sherrill-Mix, John K. Everett, Shantan Reddy, Joseph A. Fraietta, David L. Porter, Noelle Frey, Saar I. Gill, Stephan A. Grupp, Shannon L. Maude, Donald L. Siegel, Bruce L. Levine, Carl H. June, Simon F. Lacey, J. Joseph Melenhorst, Frederic D. Bushman
Journal: Journal of Clinical Investigation (2019)

Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.
Early Broad-Spectrum Antibiotics and Risk of Acute Graft-Versus-Host Disease in Children: An Analysis from the Center for International Blood and Marrow Transplantation Research (CIBMTR) and the Pediatric Health Information System (PHIS)
Authors: Caitlin W Elgarten, Yimei Li, Yuan-Shung V. Huang, Richard Aplenc, Michael T. Hemmer, Mukta Arora, Stephen R. Spellman, Tao Wang, Madan Jagasia, Margaret L. MacMillan, Joseph Pidala, Brian T. Fisher, Matt Hall
Journal: Blood (2019)
Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial
Authors: Andrew M Brunner, Traci M Blonquist, Daniel J DeAngelo, Malgorzata McMasters, Geoffrey Fell, Nicole M Hermance, Eric S Winer, R Coleman Lindsley, Gabriela S Hobbs, Philip C Amrein, Hanno R Hock, David P Steensma, Jacqueline S Garcia, Marlise R Luskin, Richard M Stone, Karen K Ballen, Jacalyn Rosenblatt, David Avigan, Myrna R Nahas, Lourdes M Mendez, Steven L McAfee, Jenna A Moran, Meghan Bergeron, Julia Foster, Christina Bertoli, Amity L Manning, Kristin L McGregor, Kaitlyn M Fishman, Frank C Kuo, Michele T Baltay, Molly Macrae, Meghan Burke, Tanya Behnan, Margaret C Wey, Tina T Som, Aura Y Ramos, Jessica Rae, Jennifer Lombardi Story, Nicole Nelson, Emma Logan, Christine Connolly, Donna S Neuberg, Yi-Bin Chen, Timothy A Graubert, Amir T Fathi
Journal: The Lancet Haematology (2019)
Brain Cancer Triage Test Advances
Authors: Jennifer Abbasi
Journal: JAMA (2019)

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Treatment (TX) Patterns Of Patients with Advanced Renal Cell Carcinoma (aRCC) Receiving First-Line (1L) TX: Results from a Cross-Sectional Real-World Study
Authors: G. Zanotti, R. Kim, S.P. Krulewicz, J.P. Hall, A. Leith, A. Bailey, F. Liu, M. Kearney
Journal: Annals of Oncology (2019)
Abstract I07: Multimodal evolutionary dynamics of pancreatic cancer
Authors: Christine Iacobuzio-Donahue
Journal: Cancer Research (2019)

Abstract The pancreatic cancer genome has been well annotated through multiple large-scale efforts. However, the extent to which specific genes correspond to specific subtypes of PDA or to specific patterns of failure remains a work in progress. Transcriptional subtypes of PDA have also emerged as an important variable for this disease, with classical-type and basal-like profiles now recognized as potential extremes of a range of phenotypes. We integrated evolutionary analysis and expression profiling in multiregion sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq defined basal-like subtype. In patients with coexisting basal/squamous and classical/glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical/glandular tumor. Cancers with squamous features were notable for MYC amplification. We also identify entosis, a unique form of cell competition in which one cancer cell engulfs another, as a predominant feature of squamous morphology in PDAC. Entosis is associated with profound intercellular heterogeneity for MYC copy number, suggesting a mechanistic link between MYC amplification, cell competition and the microenvironment in squamous features. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology, and genomic alterations in the context of clonal evolution of pancreatic cancer. Citation Format: Christine Iacobuzio-Donahue. Multimodal evolutionary dynamics of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I07.
Treatment of aortoduodenal syndrome with endoscopic ultrasound-guided gastroenterostomy
Authors: Khanh Do-Cong Pham, Roald Flesland Havre
Journal: Endoscopy (2019)

Aortoduodenal syndrome is a very rare condition characterized by nausea, vomiting, abdominal pain, malnourishment, and weight loss. Aortoduodenal syndrome is caused by an upper gastrointestinal obstruction due to an abdominal aortic aneurysm. Most patients are treated with open surgery with abdominal aortic aneurysm repair and gastro-enteral anastomosis or endovascular therapy [1] [2] [3]. Endoscopic ultrasound (EUS)-guided gastrojejunostomy with lumen-apposing metallic stents (LAMS) is a technique to create a fistula between the stomach and the jejunum to relieve symptoms in case of gastric outlet obstruction. We describe the first case of aortoduodenal syndrome managed endoscopically with EUS-guided gastroenterostomy.
Dual blockade of IL‐4 and IL‐13 with dupilumab, an IL‐4Rα antibody, is required to broadly inhibit type 2 inflammation
Authors: Audrey Le Floc’h, Jeanne Allinne, Kirsten Nagashima, George Scott, Dylan Birchard, Seblewongel Asrat, Yu Bai, Wei Keat Lim, Joel Martin, Tammy Huang, Terra B. Potocky, Jee H. Kim, Ashique Rafique, Nicholas J. Papadopoulos, Neil Stahl, George D. Yancopoulos, Andrew J. Murphy, Matthew A. Sleeman, Jamie M. Orengo
Journal: Allergy (2019)

Abstract Background Dupilumab, a fully human monoclonal antibody that binds IL‐4Rα and inhibits signaling of both IL‐4 and IL‐13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL‐4 and IL‐13 in type 2 inflammation and report dupilumab mechanisms of action. Methods Using primary cell assays and a mouse model of house dust mite–induced asthma, we compared IL‐4 vs IL‐13 vs IL‐4Rα blockers. Results Intranasal administration of either IL‐4 or IL‐13 confers an asthma‐like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head‐to‐head studies, either IL‐4 or IL‐13 inhibition to dual IL‐4/IL‐13 inhibition, we demonstrate that blockade of both IL‐4 and IL‐13 is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Notably, only dual IL‐4/IL‐13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology. Conclusions Overall, these data support IL‐4 and IL‐13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL‐4/IL‐13 blocker, in multiple type 2 diseases.
New Toxicology Tools and the Emerging Paradigm Shift in Environmental Health Decision-Making
Authors: Gary L. Ginsberg, Kristi Pullen Fedinick, Gina M. Solomon, Kevin C. Elliott, John J. Vandenberg, Stan Barone, John R. Bucher
Journal: Environmental Health Perspectives (2019)

Background: Numerous types of rapid toxicity or exposure assays and platforms are providing information relevant to human hazard and exposure identification. They offer the promise of aiding decision-making in a variety of contexts including the regulatory management of chemicals, evaluation of products and environmental media, and emergency response. There is a need to consider both the scientific validity of the new methods and the values applied to a given decision using this new information to ensure that the new methods are employed in ways that enhance public health and environmental protection. In 2018, a National Academies of Sciences, Engineering, and Medicine (NASEM) workshop examined both the toxicological and societal aspects of this challenge. Objectives: Our objectives were to explore the challenges of adopting new data streams into regulatory decision-making and highlight the need to align new methods with the information and confidence needs of the decision contexts in which the data may be applied. Methods: We go beyond the NASEM workshop to further explore the requirements of different decision contexts. We also call for the new methods to be applied in a manner consistent with the core values of public health and environmental protection. We use the case examples presented in the NASEM workshop to illustrate a range of decision contexts that have applied or could benefit from these new data streams. Organizers of the NASEM workshop came together to further evaluate the main themes from the workshop and develop a joint assessment of the critical needs for improved use of emerging toxicology tools in decision-making. We have drawn from our own experience and individual decision or research contexts as well as from the case studies and panel discussions from the workshop to inform our assessment. Discussion: Many of the statutes that regulate chemicals in the environment place a high priority on the protection of public health and the environment. Moving away from the sole reliance on traditional approaches and information sources used in hazard, exposure, and risk assessment, toward the more expansive use of rapidly acquired chemical information via in vitro, in silico, and targeted testing strategies will require careful consideration of the information needed and values considerations associated with a particular decision. In this commentary, we explore the ability and feasibility of using emerging data streams, particularly those that allow for the rapid testing of a large number of chemicals across numerous biological targets, to shift the chemical testing paradigm to one in which potentially harmful chemicals are more rapidly identified, prioritized, and addressed. Such a paradigm shift could ultimately save financial and natural resources while ensuring and preserving the protection of public health. https://doi.org/10.1289/EHP4745
CMR DENSE and the Seattle Heart Failure Model Inform Survival and Arrhythmia Risk After CRT
Authors: Kenneth C. Bilchick, Daniel A. Auger, Mohammad Abdishektaei, Roshin Mathew, Min-Woong Sohn, Xiaoying Cai, Changyu Sun, Aditya Narayan, Rohit Malhotra, Andrew Darby, J. Michael Mangrum, Nishaki Mehta, John Ferguson, Sula Mazimba, Pamela K. Mason, Christopher M. Kramer, Wayne C. Levy, Frederick H. Epstein
Journal: JACC. Cardiovascular imaging (2019)
Abstract C01: Porcupine inhibition redirects mitochondrial metabolism in Wnt-dependent pancreatic cancer
Authors: Kristina Y. Aguilera, Rana Riahi, Edris A. Saadat, Anna R. Lay, Thuc Le, Timothy R. Donahue, Caius Radu, David W. Dawson
Journal: Cancer Research (2019)

Abstract Wnt/β-catenin signaling plays important roles in pancreatic ductal adenocarcinoma (PDA) tumor initiation and progression via broad-ranging effects on proliferation, differentiation, survival, and stemness. Although Wnt has been shown to promote glycolysis in colon cancer, its role in regulating metabolism in PDA has not been well explored. For this study, RNF43-mutant cell lines were selected as exemplars of ligand-dependent autocrine Wnt signaling in PDA. These cell lines harbor an inactivating mutation in RNF43 that confers Wnt growth-dependency and response to LGK974, a PORCN inhibitor that blocks Wnt ligand secretion and signaling. Global transcriptomic, proteomic, and metabolomic analysis revealed several metabolites and putative mediators of metabolism that are directly or indirectly linked to autocrine Wnt signaling. Pharmacologic inhibition of Wnt by LGK974 led to the accumulation of pyruvate and lactate, as well as reduced tricarboxylic acid cycle metabolites and decreased mitochondrial membrane potential as measured by tetramethylrhodamine and JC-1 assays. These metabolic changes were accompanied by cell cycle arrest and downregulation of transcriptional programs involved in cell cycle progression, DNA replication, and nucleotide metabolism. Importantly, LGK974 results were phenocopied by siRNA-mediated knockdown of WNT7B and rescued with WNT3A conditioned media. Thus, inhibition of mitochondrial oxidative phosphorylation by LGK974 in RNF43-mutant PDA appears linked to its inhibition of canonical Wnt signaling, an adaptation and potential metabolic vulnerability that could be leveraged to therapeutic advantage via combinatorial strategies. Altogether, these results suggest tissue context and mechanisms of Wnt pathway activation may profoundly influence its role in regulating cancer metabolism. Citation Format: Kristina Y. Aguilera, Rana Riahi, Edris A. Saadat, Anna R. Lay, Thuc Le, Timothy R. Donahue, Caius Radu, David W. Dawson. Porcupine inhibition redirects mitochondrial metabolism in Wnt-dependent pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C01.
Abstract A34: Suppression of dystroglycan function is a hallmark of acinar-to-ductal metaplasia and favors the development of neoplasias and PDAC
Authors: Ge Huang, Christian Lanciault, Rosalie Sears, John Muschler
Journal: Cancer Research (2019)

Abstract The basement membrane (BM) is a predominant microenvironmental factor of the precancerous exocrine pancreas, and evidence suggests that the BM functions not only as a barrier to tumor cell invasion but also as an active tumor-suppressing signaling substrate. However, the molecular underpinnings of such a mechanism have not been resolved. Here we explore the expression and function of the prominent BM receptor dystroglycan (DG) in the normal pancreas and pancreatic disease. We show that DG is highly expressed in the acinar compartment of the normal pancreas; however, there is a strong suppression of DG expression with acinar-to-ductal metaplasia (ADM) in chronic pancreatitis and in all stages of pancreatic cancer evolution, from ADM to neoplasias to adenocarcinoma. The conditional knockout of DG in the murine pancreas produced no evidence of developmental or functional deficiency. However, deletion of DG expression in the context of oncogenic Kras expression (p48-Cre;KrasG12D) led to a clear acceleration of disease, including accelerated PanIN formation and an increased incidence of adenocarcinoma and metastases. Disease acceleration was accompanied by neoplasias with a strongly cystic morphology. These data establish DG as a potent suppressor of pancreatic neoplasias and cancers, and one that is muted in chronic pancreatitis and at the earliest stages of oncogenic transformation. We conclude that DG is a key mediator of the tumor-suppressing functions of the normal BM, and that maintenance or restoration of DG function is a potential target for the delay or prevention of pancreatic cancer evolution. Citation Format: Ge Huang, Christian Lanciault, Rosalie Sears, John Muschler. Suppression of dystroglycan function is a hallmark of acinar-to-ductal metaplasia and favors the development of neoplasias and PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A34.
Abstract B45: IL35/STAT3 axis as regulator of tolerance and T-cell exclusion in pancreatic cancer
Authors: Bhalchandra Mirlekar, Daniel Michaud, Yuliya Pylayeva-Gupta
Journal: Cancer Research (2019)

Abstract Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy refractory to immunotherapeutic interventions. The mechanisms that drive robust immunosuppression and CD8+ T-cell dysfunction in PDA are not well known. Using the Kras- and p53-driven mouse model of pancreatic cancer, we show that activation of IL35/STAT3 pathways directs reprogramming of suppressive regulatory B-cell lineage and inhibits CD8+ T cells via suppression of gene program that regulates infiltration and effector function. Activation of STAT3 in CD8+ T cells is driven by B cell, but not Treg-specific production of cytokine IL35. Targeting IL35 via cell lineage-specific deletion or therapeutic anti-IL35 blockade converts PDA from CD8+ T cell low to high tumor and confers sensitivity to anti-PD1 immunotherapy. Therapeutic inhibition of STAT signaling in tumor-educated CD8+ T cells improves PDA growth control upon adoptive transfer to tumor-bearing animals. Finally, we identify IL35+ B cell subset in patients with PDA and demonstrate that the presence of IL35+ cells in tumor samples predicts increased occurrence of dysfunctional CD8+ T cells. Together, these data identify IL35/STAT3 signaling as an important mediator of immune tolerance and a direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA. Citation Format: Bhalchandra Mirlekar, Daniel Michaud, Yuliya Pylayeva-Gupta. IL35/STAT3 axis as regulator of tolerance and T-cell exclusion in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B45.
T-Cell Derived Interferon Gamma Directly Targets Intestinal Epithelium to Induce Stem Cell Apoptosis in GI Gvhd
Authors: Shuichiro Takashima, Maria L. Martin, Suze A. Jansen, Ya-Yuan Fu, Anastasiya Egorova, Chen Liu, Richard Kolesnick, Caroline A. Lindemans, Alan M. Hanash
Journal: Blood (2019)
Abstract 15646: Contraction Force Analysis Using Optical Imaging in Normal and Mybpc3-Mutated iPSC-Derived Cardiomyocytes Grown on Matrices With Tunable Stiffness
Authors: Julia Hofmann, Otto Mulleners, Tessa Noordermeer, Juancito van Leeuwen, Oscar Bartulos, Pieter Voskamp, Stefan Braam, Zeno Guttenberg, Jan Danser, Danielle Majoor-Krakauer, Ingrid van der Pluijm, Erik Meijering, Jeroen Essers
Journal: Circulation (2018)

Introduction: Mutations in MYBPC3 (Myosin Binding Protein C) underlie 40% of hypertrophic cardiomyopathy cases in The Netherlands. MYBPC3 codes for the thick filament associated protein cardiac myo...
Imaging in patients with suspected acute heart failure: timeline approach position statement on behalf of the Heart Failure Association of the European Society of Cardiology
Authors: Jelena Čelutkienė, Mitja Lainscak, Lisa Anderson, Etienne Gayat, Julia Grapsa, Veli‐Pekka Harjola, Robert Manka, Petros Nihoyannopoulos, Pasquale Perrone Filardi, Rosa Vrettou, Stefan D. Anker, Gerasimos Filippatos, Alexandre Mebazaa, Marco Metra, Massimo Piepoli, Frank Ruschitzka, Jose Luis Zamorano, Giuseppe Rosano, Petar Seferovic
Journal: European Journal of Heart Failure (2019)
Everyday sunscreen use may compromise vitamin D in temperate climes: reply from authors
Authors: A.R. Young, T. Passeron
Journal: British Journal of Dermatology (2019)

Linked Articles: Passeron et al. Br J Dermatol 2019; 181:916–31. de Gruijl et al.Br J Dermatol 2020; 182:1312–3.