tbuckley/cabot-search huggingface dataset:
Dissecting the transcriptome in cardiovascular disease
Authors: Emma L Robinson, Andrew H Baker, Mairi Brittan, Ian McCracken, G Condorelli, C Emanueli, P K Srivastava, C Gaetano, T Thum, M Vanhaverbeke, C Angione, S Heymans, Y Devaux, T Pedrazzini, F Martelli
Journal: Cardiovascular Research (2021)

The human transcriptome comprises a complex network of coding and non-coding RNAs implicated in a myriad of biological functions. Non-coding RNAs exhibit highly organized spatial and temporal expression patterns and are emerging as critical regulators of differentiation, homeostasis, and pathological states, including in the cardiovascular system. This review defines the current knowledge gaps, unmet methodological needs, and describes the challenges in dissecting and understanding the role and regulation of the non-coding transcriptome in cardiovascular disease. These challenges include poor annotation of the non-coding genome, determination of the cellular distribution of transcripts, assessment of the role of RNA processing and identification of cell-type specific changes in cardiovascular physiology and disease. We highlight similarities and differences in the hurdles associated with the analysis of the non-coding and protein-coding transcriptomes. In addition, we discuss how the lack of consensus and absence of standardized methods affect reproducibility of data. These shortcomings should be defeated in order to make significant scientific progress and foster the development of clinically applicable non-coding RNA-based therapeutic strategies to lessen the burden of cardiovascular disease.
P60.01 Single-Cell Transcriptomics to Assess Response to Immunotherapy in Advanced Lung Cancer ex-vivo: Developing a Functional Predictive Assay
Authors: V. Chin, E. Stone, A. Havryk, M. Plit, R. Mccloy, A. Murphy, A. Field, N. Watkins, J. Powell
Journal: Journal of Thoracic Oncology (2021)
Thiol-reactive compounds as topoisomerase I catalytic inhibitors
Authors: Danièle Montaudon, Laurent P. Rivory, Annick Larrue, Jacques Robert, Céline Douat-Casassus, Stéphane Quideau, Philippe Pourquier
Journal: Cancer Research (2005)

2393  DNA topoisomerase I (top1) is a nuclear enzyme that plays a crucial role in the removal of DNA supercoiling associated with replication and transcription. It is the target of two classes of inhibitors: top1 poisons such as camptothecins (CPT) which inhibit top1-mediated religation and top1 suppressors which exert their cytotoxicity by preventing binding of the enzyme to the DNA and/or the cleavage step of the top1 reaction. Top1 contains eight cysteines, including two vicinal residues (cys504 & 505) that are extremely conserved among eukaryotes. All are located in two domains that are essential for enzyme activity. In this study we show that these cysteines are potential target of thiol-reactive compounds such as N-ethylmaleimide (NEM) and phenylarsine oxyde (PAO). Using purified human top1, we show that thiol reactants can inhibit top1 catalytic activity. Using oligonucleotides containing a unique top1 cleavage site, we demonstrated that thiolation of the enzyme resulted in a strong inhibition of the cleavage step of the top1 reaction without modifying binding of the enzyme to the DNA. This inhibition was more pronounced when top1 was preincubated with the thiol-reactive compound and could be reversed in the presence of dithiothreitol. Interestingly, PAO, which is known to specifically react with vicinally-spaced cysteines, was active at much lower concentrations than NEM suggesting the involvement of vicinally-spaced cysteines. In view of the recent crystal structure of top1 in non-covalent form with DNA, we surmised that cys504 and 505 could be good candidates for PAO-crosslinking since they are located on a loop with sulfur-to-sulfur distance that is compatible with the formation of a dithioarsine nine-membered ring. All together, our results suggest that the conserved cysteines of top1 may play a critical role in enzyme catalytic activity, and that thiol-reactive compounds may be used as efficient top1 catalytic inhibitors.
Integrated Screens Identify CDK1 as a Therapeutic Target in Advanced Gastrointestinal Stromal Tumors
Authors: Xiaojing Lu, Yuzhi Pang, Hui Cao, Xiaoxiao Liu, Lin Tu, Yanying Shen, Xiaona Jia, Jen-Chieh Lee, Yuexiang Wang
Journal: Cancer Research (2021)

Oncogenic KIT or PDGFRA receptor tyrosine kinase mutations are compelling therapeutic targets in gastrointestinal stromal tumor (GIST), and treatment with the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with advanced GIST. Polyclonal emergence of KIT/PDGFRA secondary mutations is the main mechanism of imatinib progression, making it challenging to overcome KIT/PDGFRA-inhibitor resistance. It is unclear whether there are other therapeutic targets in advanced GIST. Using genome-wide transcriptomic profiling of advanced versus early-stage GIST and CRISPR knockout functional screens, we demonstrate that CDK1 is frequently highly expressed in advanced GIST but not in early-stage GIST across three patient cohorts. High expression of CDK1 was associated with malignancy in GIST. CDK1 was critically required for advanced GIST, including imatinib-resistant GIST. CDK1 ablation led to robust proliferation inhibition. A mass spectrometry-based proteomics screen further revealed that AKT is a novel substrate of CDK1 kinase in GIST. CDK1 bound AKT and regulated its phosphorylation, thereby promoting GIST proliferation and progression. Importantly, a pharmacologic inhibitor of CDK1, RO-3306, disrupted GIST cell proliferation in CDK1 highly expressed GIST but not in CDK1-negative GIST cells and nontransformed fibroblast cells. Treatment with RO-3306 reduced tumor growth in both imatinib-resistant and imatinib-sensitive GIST xenograft mouse models. Our findings suggest that CDK1 represents a druggable therapeutic target in GIST and warrants further testing in clinical trials. SIGNIFICANCE: These findings propose CDK1 as a novel cell-cycle-independent vulnerability in gastrointestinal stromal tumors, representing a new therapeutic opportunity for patients with advanced disease.
Progression of Frailty in Survivors of Childhood Cancer: A St. Jude Lifetime Cohort Report
Authors: Angela Delaney, Carrie R Howell, Kevin R Krull, Tara M Brinkman, Gregory T Armstrong, Wassim Chemaitilly, Carmen L Wilson, Daniel A Mulrooney, Zhaoming Wang, Jennifer Q Lanctot, Ruth E Johnson, Matthew R Krull, Robyn E Partin, Kyla C Shelton, Deo Kumar Srivastava, Leslie L Robison, Melissa M Hudson, Kirsten K Ness
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at 10 or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail. Methods Frailty was measured at study entry and 5 years later. Logistic regression tested the associations of several factors with having frailty at 5 years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates. Results Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were ages 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0% to 7.5%) to 13.6% (95% CI = 11.9% to 15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation 20 Gy or higher (odds ratio [OR] = 1.98, 95% CI = 1.29 to 3.05), cardiac (OR = 1.58, 95% CI = 1.02 to 2.46), and neurological (OR = 2.58, 95% CI = 1.69 to 3.92) conditions; lack of strength training (OR = 1.74, 95% CI = 1.14 to 2.66); sedentary lifestyle (OR = 1.75, 95% CI = 1.18 to 2.59); and frailty at study entry (OR = 11.12, 95% CI = 6.64 to 18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95 to 6.32). Conclusions Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle, may decrease risk of adverse health events and improve longevity in survivors.
Intensified treatment of patients with early stage, unfavourable Hodgkin lymphoma: long-term follow-up of a randomised, international phase 3 trial of the German Hodgkin Study Group (GHSG HD14)
Authors: Sarah Gillessen, Annette Plütschow, Michael Fuchs, Jana Markova, Richard Greil, Max S Topp, Julia Meissner, Josée M Zijlstra, Dennis A Eichenauer, Paul J Bröckelmann, Volker Diehl, Peter Borchmann, Andreas Engert, Bastian von Tresckow
Journal: The Lancet Haematology (2021)
Surface Proteomics Reveals CD72 as a Target for <i>In Vitro</i>–Evolved Nanobody-Based CAR-T Cells in <i>KMT2A/MLL1</i>-Rearranged B-ALL
Authors: Matthew A. Nix, Kamal Mandal, Huimin Geng, Neha Paranjape, Yu-Hsiu T. Lin, Jose M. Rivera, Makeba Marcoulis, Kristie L. White, Jeffrey D. Whitman, Sagar P. Bapat, Kevin R. Parker, Jonathan Ramirez, Anne Deucher, Paul Phojanokong, Veronica Steri, Faranak Fattahi, Byron C. Hann, Ansuman T. Satpathy, Aashish Manglik, Elliot Stieglitz, Arun P. Wiita
Journal: Cancer Discovery (2021)

Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully in vitro system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL. SIGNIFICANCE: Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully in vitro nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development.This article is highlighted in the In This Issue feature, p. 1861.
P75.10 Risk Factors for Immune-Related Adverse Events from Anti-PD-1/PD-L1 Treatment in an Asian Cohort of NSCLC Patients
Authors: Y. Huang, Y.Y. Soon, F. Aminkeng, S.H. Tay, Y. Ang, B.C. Goh, A. Wong, R.A. Soo
Journal: Journal of Thoracic Oncology (2021)
Very little influenza in the WHO European Region during the 2020/21 season, weeks 40 2020 to 8 2021
Authors: Cornelia Adlhoch, Piers Mook, Favelle Lamb, Lisa Ferland, Angeliki Melidou, Andrew J Amato-Gauci, Richard Pebody
Journal: Eurosurveillance (2021)

Between weeks 40 2020 and 8 2021, the World Health Organization European Region experienced a 99.8% reduction in sentinel influenza virus positive detections (33/25,606 tested; 0.1%) relative to an average of 14,966/39,407 (38.0%; p &lt; 0.001) over the same time in the previous six seasons. COVID-19 pandemic public health and physical distancing measures may have extinguished the 2020/21 European seasonal influenza epidemic with just a few sporadic detections of all viral subtypes. This might possibly continue during the remainder of the influenza season.
P77.02 Efficacy of Tiragolumab + Atezolizumab in PD-L1 IHC and TIGIT Subgroups in the Phase II CITYSCAPE Study in First-Line NSCLC
Authors: N. Patil, B.C. Cho, M. Johnson, R.B. Caro, A. Spira, C. Chiu, N. Molden, T. Pham, X. Yang, Y. Choi, Z. Zhang, T. Hoang, M. Ballinger, R. Meng, D. Rodríguez-Abreu
Journal: Journal of Thoracic Oncology (2021)
P25.11 Evaluation of the Safety of Tumor Treating Fields (TTFields) Application to the Torso – in Vivo Studies
Authors: S. Davidi, R. Blatt, M. Munster, A. Shteingauz, S. Cahal, M. Giladi, U. Weinberg, Y. Palti
Journal: Journal of Thoracic Oncology (2021)
P12.03 Public Versus Private Care Patients Treated in the Same Hospital. Are the Patients the Same?
Authors: L. Bittencourt Hinrichsen, M.T. Tsukazan, A. Vigo, M. Iglesias, R. Ribeiro, L.E. Canton, A.H. Furlanetto, P.A. Schulze, G.F. Schneider, M.L. Santos, J.A. Figueiredo Pinto
Journal: Journal of Thoracic Oncology (2021)
Racial/Ethnic Disparities in Interhospital Transfer for Conditions With a Mortality Benefit to Transfer Among Patients With Medicare
Authors: Evan Michael Shannon, Jie Zheng, E. John Orav, Jeffrey L. Schnipper, Stephanie K. Mueller
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Interhospital transfer (IHT) of patients is a common occurrence in modern health care. Racial/ethnic disparities are prevalent throughout US health care, but their presence in IHT is not well characterized. <h3>Objective</h3> To determine if there are racial/ethnic disparities in IHT for medical diagnoses for which IHT is associated with a mortality benefit. <h3>Design, Setting, and Participants</h3> This cross-sectional analysis used 2013 data from the Center for Medicare &amp; Medicaid Services 100% Master Beneficiary Summary and Inpatient Claims merged with 2013 American Hospital Association data. Individuals with Medicare aged 65 years or older continuously enrolled in Medicare Part A and B with an inpatient hospitalization claim in 2013 for primary diagnosis of acute myocardial infarction, stroke, sepsis, or respiratory diseases were included. Data analysis occurred from November 2019 through July 2020. <h3>Exposures</h3> Race/ethnicity. <h3>Main Outcomes and Measures</h3> The primary outcome of interest was IHT. For the primary analysis, a series of logistic regression models were created to estimate the adjusted odds of IHT for Black and Hispanic patients compared with White patients, controlling for patient clinical and demographic variables and incorporating hospital fixed effects. In secondary analyses, subgroup analyses were conducted by diagnosis, hospital teaching status, and hospitalization to hospitals in the top decile of Black and Hispanic patient proportion. <h3>Results</h3> Among 899 557 patients, 734 958 patients were White (81.7%), 84 544 patients were Black (9.4%), and 47 588 patients were Hispanic (5.3%); there were 418 683 men (46.5%), and 306 215 patients (34.0%) were older than 84 years. The mean (SD) age was 76.8 (7.5) years. Among all patients, 20 171 White patients (2.7%), 1913 Black patients (2.3%), and 1062 Hispanic patients (2.2%) underwent IHT. After controlling for patient variables and hospital fixed effects, Black patients had a persistently lower odds of IHT (adjusted odds ratio, 0.87; 95% CI, 0.81-0.92;<i>P</i> &lt; .001), while Hispanic patients had higher odds of IHT (adjusted odds ratio, 1.14; 95% CI, 1.05-1.24;<i>P</i> = .002) compared with White patients. <h3>Conclusions and Relevance</h3> This national evaluation of IHT among patients hospitalized with diagnoses previously found to have mortality benefit with transfer found that, compared with White patients, Black patients had persistently lower adjusted odds of transfer after accounting for patient and hospital characteristics and measured across various hospital settings. Meanwhile, Hispanic patients had higher adjusted odds of transfer. This research highlights the need for the development of strategies to mitigate disparate transfer practices by patient race/ethnicity.
Minimal SARS-CoV-2 Transmission After Implementation of a Comprehensive Mitigation Strategy at a School — New Jersey, August 20–November 27, 2020
Authors: Kevin G. Volpp, Bruce H. Kraut, Smita Ghosh, John Neatherlin
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

During fall 2020, many U.S. kindergarten through grade 12 (K-12) schools closed campuses and instituted remote learning to limit in-school transmission of SARS-CoV-2, the virus that causes COVID-19 (1,2). A New Jersey grade 9-12 boarding school with 520 full-time resident students, 255 commuter students, and 405 faculty and staff members implemented a comprehensive mitigation strategy that included universal masking, testing, upgraded air-handling equipment to improve ventilation, physical distancing of ≥6 ft, contact tracing, and quarantine and isolation protocols to prevent and control transmission of SARS-CoV-2 among students, faculty, and staff members. Mandatory twice-weekly screening using real-time reverse transcription-polymerase chain reaction (RT-PCR) testing of all students and staff members during August 20-November 27, 2020, resulted in the testing of 21,449 specimens. A total of 19 (5%) of 405 faculty and staff members and eight (1%) of 775 students received positive test results; only two identified cases were plausibly caused by secondary transmission on campus. Comprehensive mitigation approaches including frequent testing and universal masking can help prevent outbreaks in in-person high school settings even when community transmission is ongoing.
FP10.04 RESILIENT Part 1: Safety and Efficacy of Second-Line Liposomal Irinotecan in Patients with Small Cell Lung Cancer
Authors: L. Paz-Ares, D.R. Spigel, Y. Chen, M. Jove, O. Juan-Vidal, P. Rich, T. Hayes, V. Gutiérrez Calderón, R.B. Caro, A. Navarro, A. Dowlati, B. Zhang, Y. Moore, X. Yao, J. Kokhreidze, S. Ponce, P. Bunn
Journal: Journal of Thoracic Oncology (2021)
Engineering Vascularized Organoid-on-a-Chip Models
Authors: Venktesh S. Shirure, Christopher C.W. Hughes, Steven C. George
Journal: Annual Review of Biomedical Engineering (2021)

Recreating human organ–level function in vitro is a rapidly evolving field that integrates tissue engineering, stem cell biology, and microfluidic technology to produce 3D organoids. A critical component of all organs is the vasculature. Herein, we discuss general strategies to create vascularized organoids, including common source materials, and survey previous work using vascularized organoids to recreate specific organ functions and simulate tumor progression. Vascularization is not only an essential component of individual organ function but also responsible for coupling the fate of all organs and their functions. While some success in coupling two or more organs together on a single platform has been demonstrated, we argue that the future of vascularized organoid technology lies in creating organoid systems complete with tissue-specific microvasculature and in coupling multiple organs through a dynamic vascular network to create systems that can respond to changing physiological conditions.
Delivery of cancer therapies by synthetic and bio-inspired nanovectors
Authors: Tina Briolay, Tacien Petithomme, Morgane Fouet, Nelly Nguyen-Pham, Christophe Blanquart, Nicolas Boisgerault
Journal: Molecular Cancer (2021)

Abstract Background As a complement to the clinical development of new anticancer molecules, innovations in therapeutic vectorization aim at solving issues related to tumor specificity and associated toxicities. Nanomedicine is a rapidly evolving field that offers various solutions to increase clinical efficacy and safety. Main Here are presented the recent advances for different types of nanovectors of chemical and biological nature, to identify the best suited for translational research projects. These nanovectors include different types of chemically engineered nanoparticles that now come in many different flavors of ‘smart’ drug delivery systems. Alternatives with enhanced biocompatibility and a better adaptability to new types of therapeutic molecules are the cell-derived extracellular vesicles and micro-organism-derived oncolytic viruses, virus-like particles and bacterial minicells. In the first part of the review, we describe their main physical, chemical and biological properties and their potential for personalized modifications. The second part focuses on presenting the recent literature on the use of the different families of nanovectors to deliver anticancer molecules for chemotherapy, radiotherapy, nucleic acid-based therapy, modulation of the tumor microenvironment and immunotherapy. Conclusion This review will help the readers to better appreciate the complexity of available nanovectors and to identify the most fitting “type” for efficient and specific delivery of diverse anticancer therapies.
P76.58 Osimertinib for EGFR-Positive NSCLC Patients with Leptomeningeal Metastases Harboring T790M-Positive or T790M-Negative Mutations
Authors: H. Xu, Y. Zhang, J. Kong, G. Yang, L. Yang, S. Liu, Y. Wang
Journal: Journal of Thoracic Oncology (2021)
New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation
Authors: Martin Aguilar, Robert A Rose, Abhijit Takawale, Stanley Nattel, Svetlana Reilly
Journal: Cardiovascular Research (2021)

Abstract Hormones are potent endo-, para-, and autocrine endogenous regulators of the function of multiple organs, including the heart. Endocrine dysfunction promotes a number of cardiovascular diseases, including atrial fibrillation (AF). While the heart is a target for endocrine regulation, it is also an active endocrine organ itself, secreting a number of important bioactive hormones that convey significant endocrine effects, but also through para-/autocrine actions, actively participate in cardiac self-regulation. The hormones regulating heart-function work in concert to support myocardial performance. AF is a serious clinical problem associated with increased morbidity and mortality, mainly due to stroke and heart failure. Current therapies for AF remain inadequate. AF is characterized by altered atrial function and structure, including electrical and profibrotic remodelling in the atria and ventricles, which facilitates AF progression and hampers its treatment. Although features of this remodelling are well-established and its mechanisms are partly understood, important pathways pertinent to AF arrhythmogenesis are still unidentified. The discovery of these missing pathways has the potential to lead to therapeutic breakthroughs. Endocrine dysfunction is well-recognized to lead to AF. In this review, we discuss endocrine and cardiocrine signalling systems that directly, or as a consequence of an underlying cardiac pathology, contribute to AF pathogenesis. More specifically, we consider the roles of products from the hypothalamic-pituitary axis, the adrenal glands, adipose tissue, the renin–angiotensin system, atrial cardiomyocytes, and the thyroid gland in controlling atrial electrical and structural properties. The influence of endocrine/paracrine dysfunction on AF risk and mechanisms is evaluated and discussed. We focus on the most recent findings and reflect on the potential of translating them into clinical application.