tbuckley/cabot-search huggingface dataset:
COVID-19 and immune checkpoint inhibitors: initial considerations
Authors: Ryan J Sullivan, Douglas B Johnson, Brian I Rini, Tomas G Neilan, Christine M Lovly, Javid J Moslehi, Kerry L Reynolds
Journal: Journal for ImmunoTherapy of Cancer (2020)

<h3>Abstract</h3> COVID-19 infections are characterized by inflammation of the lungs and other organs that ranges from mild and asymptomatic to fulminant and fatal. Patients who are immunocompromised and those with cardiopulmonary comorbidities appear to be particularly afflicted by this illness. During pandemic conditions, many aspects of cancer care have been impacted. One important clinical question is how to manage patients who need anticancer therapy, including immune checkpoint inhibitors (ICIs) during these conditions. Herein, we consider diagnostic and therapeutic implications of using ICI during this unprecedented period of COVID-19 infections. In particular, we consider the impact of ICI on COVID-19 severity, decisions surrounding continuing or interrupting therapy, diagnostic measures in patients with symptoms or manifestations potentially consistent with either COVID-19 or ICI toxicity, and resumption of therapy in infected patients. While more robust data are needed to guide clinicians on management of patients with cancer who may be affected by COVID-19, we hope this commentary provides useful insights for the clinical community.
Antipsychotics in Adults With Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications
Authors: Lisa Hartling, Ahmed M. Abou-Setta, Serdar Dursun, Shima S. Mousavi, Dion Pasichnyk, Amanda S. Newton
Journal: Annals of Internal Medicine (2020)

This systematic review compares the benefits and harms of first- versus second-generation antipsychotics for treating adults aged 18 to 64 years with schizophrenia. Overall, few differences of clin...
The Shortage of Organs for Transplantation
Authors: A Spital
Journal: New England Journal of Medicine (1991)

THE ability to transplant solid organs successfully is one of the most miraculous accomplishments of modern medicine. For a patient with end-stage renal disease, a renal transplant offers the best chance of rehabilitation and long-term survival. Renal transplantation, which costs about one third as much as dialysis,1 is also the optimal therapy from the viewpoint of society, which now pays over $3 billion a year for the government's end-stage renal disease program.2 For those with failing hearts or livers, transplantation is even more valuable, since it is the only therapy that can replace imminent certain death with the hope of . . .
Negative Predictive Value of Multiparametric Magnetic Resonance Imaging in the Detection of Clinically Significant Prostate Cancer in the Prostate Imaging Reporting and Data System Era: A Systematic Review and Meta-analysis
Authors: Niranjan J. Sathianathen, Altan Omer, Eli Harriss, Lucy Davies, Veeru Kasivisvanathan, Shonit Punwani, Caroline M. Moore, Christof Kastner, Tristan Barrett, Roderick CN Van Den Bergh, Ben A. Eddy, Fergus Gleeson, Ruth Macpherson, Richard J. Bryant, James W.F. Catto, Declan G. Murphy, Freddie C. Hamdy, Hashim U. Ahmed, Alastair D. Lamb
Journal: European Urology (2020)
Environment-Sensing Aryl Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions
Authors: Juyong Brian Kim, Quanyi Zhao, Trieu Nguyen, Milos Pjanic, Paul Cheng, Robert Wirka, Stanislao Travisano, Manabu Nagao, Ramendra Kundu, Thomas Quertermous
Journal: Circulation (2020)

Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.We combined RNA-sequencing, chromatin immunoprecipitation followed by sequencing, assay for transposase-accessible chromatin using sequencing, and in vitro assays in human coronary artery SMCs, with single-cell RNA-sequencing, histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease.Genomic studies coupled with functional assays in cultured human coronary artery SMCs revealed that AHR modulates the human coronary artery SMC phenotype and suppresses ossification in these cells. Lineage-tracing and activity-tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMCs in the atherosclerotic lesion cap. Furthermore, single-cell RNA-sequencing studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMCs expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term "chondromyocytes," were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMCs in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout in comparison with wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses.Overall, we conclude that AHR promotes the maintenance of lesion cap integrity and diminishes the disease-related SMC-to-chondromyocyte transition in atherosclerotic tissues.
Genetics Insights in the Relationship Between Type 2 Diabetes and Coronary Heart Disease
Authors: Mark O. Goodarzi, Jerome I. Rotter
Journal: Circulation Research (2020)

Diabetes mellitus is a major risk factor for coronary heart disease (CHD). The major form of diabetes mellitus is type 2 diabetes mellitus (T2D), which is thus largely responsible for the CHD association in the general population. Recent years have seen major advances in the genetics of T2D, principally through ever-increasing large-scale genome-wide association studies. This article addresses the question of whether this expanding knowledge of the genomics of T2D provides insight into the etiologic relationship between T2D and CHD. We will investigate this relationship by reviewing the evidence for shared genetic loci between T2D and CHD; by examining the formal testing of this interaction (Mendelian randomization studies assessing whether T2D is causal for CHD); and then turn to the implications of this genetic relationship for therapies for CHD, for therapies for T2D, and for therapies that affect both. In conclusion, the growing knowledge of the genetic relationship between T2D and CHD is beginning to provide the promise for improved prevention and treatment of both disorders.
Histopathologic Features and Clinical Outcome of Anaplastic Thyroid Carcinoma with a Minor Anaplastic Component
Authors: Kristine S. Wong, Jochen H. Lorch, Erik K. Alexander, Ellen Marqusee, Nancy L. Cho, Matthew A. Nehs, Gerard M. Doherty, Justine A. Barletta
Journal: Endocrine Pathology (2020)
Transcriptomic Heterogeneity of Gleason Grade Group 5 Prostate Cancer
Authors: Amar U. Kishan, Tahmineh Romero, Mohammed Alshalalfa, Yang Liu, Phuoc T. Tran, Nicholas G. Nickols, Huihui Ye, Dipti Sajed, Matthew B. Rettig, Robert E. Reiter, Isla P. Garraway, Daniel E. Spratt, Steven J. Freedland, Xin Zhao, Ziwen Li, Matthew Deek, Julie Livingstone, Brandon A. Mahal, Paul L. Nguyen, Felix Y. Feng, Robert B. Den, Edward M. Schaeffer, Tamara L. Lotan, R. Jeffrey Karnes, Eric A. Klein, Ashley E. Ross, Tristan Grogan, Elai Davicioni, David Elashoff, Paul C. Boutros, Joanne B. Weidhaas
Journal: European Urology (2020)
Three-dimensional genome restructuring across timescales of activity-induced neuronal gene expression
Authors: Jonathan A. Beagan, Elissa D. Pastuzyn, Lindsey R. Fernandez, Michael H. Guo, Kelly Feng, Katelyn R. Titus, Harshini Chandrashekar, Jason D. Shepherd, Jennifer E. Phillips-Cremins
Journal: Nature Neuroscience (2020)
Hepatoma cell-intrinsic TLR9 activation induces immune escape through PD-L1 upregulation in hepatocellular carcinoma
Authors: Binghai Zhou, Jiuliang Yan, Lei Guo, Bo Zhang, Shuang Liu, Mincheng Yu, Zheng Chen, Kewei Zhang, Wentao Zhang, Xiaoqiang Li, Yongfeng Xu, Yongsheng Xiao, Jian Zhou, Jia Fan, Mien-Chie Hung, Hui Li, Qinghai Ye
Journal: Theranostics (2020)

A TLR9 agonist in combination with a PD-1 inhibitor produced powerful antitumor responses in a clinical trial despite TLR9 agonists as monotherapies failing to generate systemic antitumor immune responses due to immunosuppressive effects.However, the mechanism involved in the improved response induced by their combination remains unknown.Methods: Subcutaneous and orthotopic Hepa1-6 tumor model was used for single-drug and combined-drug treatment.We used TLR9 agonist stimulation or lentiviral vectors to overexpress TLR9 and activate TLR9 signaling.We next investigated the crosstalk between PARP1 autoPARylation and ubiquitination and between STAT3 PARylation and phosphorylation mediated by TLR9.Tissue chips were used to analyze the relationships among TLR9, PARP1, p-STAT3 and PD-L1 expression.Results: In this study, we found that the TLR9 agonist in combination with anti-PD-1 therapy or anti-PD-L1 therapy yielded an additive effect that inhibited HCC growth in mice.Mechanistically, we found that TLR9 promoted PD-L1 transcription by enhancing STAT3 Tyr705 phosphorylation.Then, we observed that TLR9 negatively regulated PARP1 expression, which mediated a decrease in STAT3 PARylation and an increase in STAT3 Tyr705 phosphorylation.Moreover, we found that TLR9 enhanced PARP1 autoPARylation by inhibiting PARG expression, which then promoted the RNF146-mediated ubiquitination and subsequent degradation of PARP1.Finally, we observed positive associations between TLR9 and p-STAT3 (Tyr705) or PD-L1 expression and negative associations between TLR9 and PARP1 in HCC patient samples.Conclusions: We showed that hepatoma cell-intrinsic TLR9 activation regulated the crosstalk between PARP1 autoPARylation and ubiquitination and between STAT3 PARylation and phosphorylation, which together upregulated PD-L1 expression and finally induces immune escape.Therefore, combination therapy with a TLR9 agonist and an anti-PD-1 antibody or anti-PD-L1 had much better antitumor efficacy than either monotherapy in HCC.
Abstract 14643: 2-Cl-C.OXT-A Stimulates Contraction Through the Suppression of PDE Activity in HiPSC-Derived Cardiac Organoids
Authors: Takahiro Kitsuka, Manabu Itoh, Sojiro Amamoto, ken-ichi Arai, Junichi Oyama, Koichi Node, Koichi Nakayama, Shigeki Morita, Takahiro Nishida
Journal: Circulation (2018)

Introduction: 2-Cl-C.OXT-A (COA-Cl) enhanced angiogenesis and improved brain function in rat stroke models. COA-Cl is known as a novel synthesized adenosine analog to activate S1P1 receptor (S1P1R)...
Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity
Authors: Sandro Marini, Katherine Crawford, Andrea Morotti, Myung J. Lee, Alessandro Pezzini, Charles J. Moomaw, Matthew L. Flaherty, Joan Montaner, Jaume Roquer, Jordi Jimenez-Conde, Eva Giralt-Steinhauer, Roberto Elosua, Elisa Cuadrado-Godia, Carolina Soriano-Tarraga, Agnieszka Slowik, Jeremiasz M. Jagiella, Joanna Pera, Andrzej Urbanik, Alexander Pichler, Björn M. Hansen, Jacob L. McCauley, David L. Tirschwell, Magdy Selim, Devin L. Brown, Scott L. Silliman, Bradford B. Worrall, James F. Meschia, Chelsea S. Kidwell, Fernando D. Testai, Steven J. Kittner, Helena Schmidt, Christian Enzinger, Ian J. Deary, Kristiina Rannikmae, Neshika Samarasekera, Rustam Al-Shahi Salman, Catherine L. Sudlow, Catharina J. M. Klijn, Koen M. van Nieuwenhuizen, Israel Fernandez-Cadenas, Pilar Delgado, Bo Norrving, Arne Lindgren, Joshua N. Goldstein, Anand Viswanathan, Steven M. Greenberg, Guido J. Falcone, Alessandro Biffi, Carl D. Langefeld, Daniel Woo, Jonathan Rosand, Christopher D. Anderson
Journal: JAMA Neurology (2019)

Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.
RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner
Authors: Xingya Guo, Kai Li, Weiliang Jiang, Yangyang Hu, Wenqin Xiao, Yinshi Huang, Yun Feng, Qin Pan, Rong Wan
Journal: Molecular Cancer (2020)

Abstract Background N6-methyladenosine (m6A) is the most abundant reversible methylation modification of eukaryotic mRNA, and it plays vital roles in tumourigenesis. This study aimed to explore the role of the m6A demethylase ALKBH5 in pancreatic cancer (PC). Methods The expression of ALKBH5 and its clinicopathological impact were evaluated in PC cohorts. The effects of ALKBH5 on the biological characteristics of PC cells were investigated on the basis of gain-of-function and loss-of-function analyses. Subcutaneous and orthotopic models further uncovered the role of ALKBH5 in tumour growth. mRNA and m6A sequencing and assays of m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the targeted effect of ALKBH5 on PER1. P53-binding sites in the ALKBH5 promoter were investigated by ChIP and luciferase assays to reveal the interplay between ALKBH5 and PER1-activated ATM-CHK2-P53/CDC25C signalling. Results ALKBH5 loss characterized the occurrence and poor clinicopathological manifestations in patients with PC. Overexpression of ALKBH5 reduced tumoural proliferative, migrative, invasive activities in vitro and ameliorated tumour growth in vivo, whereas ALKBH5 knockdown facilitated PC progression. Mechanistically, ALKBH5 posttranscriptionally activated PER1 by m6A demethylation in an m6A-YTHDF2-dependent manner. PER1 upregulation led to the reactivation of ATM-CHK2-P53/CDC25C signalling, which inhibited cell growth. P53-induced activation of ALKBH5 transcription acted as a feedback loop regulating the m6A modifications in PC. Conclusion ALKBH5 serves as a PC suppressor by regulating the posttranscriptional activation of PER1 through m6A abolishment, which may highlight a demethylation-based approach for PC diagnosis and therapy.
Compressing gene expression data using multiple latent space dimensionalities learns complementary biological representations
Authors: Gregory P. Way, Michael Zietz, Vincent Rubinetti, Daniel S. Himmelstein, Casey S. Greene
Journal: Genome biology (2020)

Abstract Background Unsupervised compression algorithms applied to gene expression data extract latent or hidden signals representing technical and biological sources of variation. However, these algorithms require a user to select a biologically appropriate latent space dimensionality. In practice, most researchers fit a single algorithm and latent dimensionality. We sought to determine the extent by which selecting only one fit limits the biological features captured in the latent representations and, consequently, limits what can be discovered with subsequent analyses. Results We compress gene expression data from three large datasets consisting of adult normal tissue, adult cancer tissue, and pediatric cancer tissue. We train many different models across a large range of latent space dimensionalities and observe various performance differences. We identify more curated pathway gene sets significantly associated with individual dimensions in denoising autoencoder and variational autoencoder models trained using an intermediate number of latent dimensionalities. Combining compressed features across algorithms and dimensionalities captures the most pathway-associated representations. When trained with different latent dimensionalities, models learn strongly associated and generalizable biological representations including sex, neuroblastoma MYCN amplification, and cell types. Stronger signals, such as tumor type, are best captured in models trained at lower dimensionalities, while more subtle signals such as pathway activity are best identified in models trained with more latent dimensionalities. Conclusions There is no single best latent dimensionality or compression algorithm for analyzing gene expression data. Instead, using features derived from different compression models across multiple latent space dimensionalities enhances biological representations.
PREVENTION OF NSAID-INDUCED GASTRIC ULCER WITH PROSTAGLANDIN ANALOGUES
Authors: A.S Taha, S Mclaughlin, P.J Holland, R.W Kelly, R.D Sturrock, R.I Russell, H.G Dammann, J Simon-Schultz, W Bauermeister, A Schmoldt, P Muller, B Simon
Journal: The Lancet (1989)
Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena
Authors: Manali Mukherjee, David Felipe Forero, Stephanie Tran, Marie-Eve Boulay, Mylène Bertrand, Anurag Bhalla, Jayant Cherukat, Hajar Al-Hayyan, Anmar Ayoub, Spencer D. Revill, Tanvi Javkar, Katherine Radford, Melanie Kjarsgaard, Chynna Huang, Anna Dvorkin-Gheva, Kjetil Ask, Ronald Olivenstein, Nandini Dendukuri, Catherine Lemiere, Louis-Philippe Boulet, James G. Martin, Parameswaran Nair
Journal: European Respiratory Journal (2020)

Background In clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50–60%. Objective To observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response. Methods In four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs. Results Suboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology. Conclusion A significant number of patients who meet currently approved indications for anti-IL5 mAbs show suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.
Vascular Risk Reduction in Obesity through Reduced Granulocyte Burden and Improved Angiogenic Monocyte Content following Bariatric Surgery
Authors: David A. Hess, Justin Z. Trac, Stephen A. Glazer, Daniella C. Terenzi, Adrian Quan, Hwee Teoh, Mohammed Al-Omran, Deepak L. Bhatt, C. David Mazer, Ori D. Rotstein, Subodh Verma
Journal: Cell Reports Medicine (2020)

Bariatric surgery, in addition to the benefit of sustained weight loss, can also reduce cardiometabolic risk and mortality. Lifelong vessel maintenance is integral to the prevention of cardiovascular disease. Using aldehyde dehydrogenase activity, an intracellular detoxifying enzyme present at high levels within pro-vascular progenitor cells, we observed an association between chronic obesity and "regenerative cell exhaustion" (RCE), a pathology whereby chronic assault on circulating regenerative cell types can result in adverse inflammation and diminished vessel repair. We also describe that, at 3 months following bariatric surgery, systemic inflammatory burden was reduced and pro-angiogenic macrophage precursor content was improved in subjects with severe obesity, suggesting the restoration of a microenvironment to support vessel homeostasis. These data suggest that bariatric surgery may reverse deleterious events that predispose patients with morbid obesity to cardiovascular risk.
Lithium Loaded Octa‐Poly(Ethylene Glycol) Based Adhesive Facilitates Axon Regeneration and Reconnection of Transected Peripheral Nerves
Authors: Yazhong Bu, Xianghai Wang, Lixia Li, Xiaofang Hu, Dandan Tan, Zhenlin Li, Muhua Lai, Xiaozhong Qiu, Feifei Sun, Hufei Wang, Fei Yang, Decheng Wu, Jiasong Guo
Journal: Advanced Healthcare Materials (2020)

At present, reconnecting the transected nerve in clinic is still mainly reliant on surgery suture. This is a procedure that requires thorough training and is also time consuming. Here, an octa-poly(ethylene glycol) (PEG)-based adhesive for fast reconnecting of the transected peripheral nerve is reported. To enhance the therapeutic efficacy, a succinyl unit is applied to endow the controllably dissolvable property of the adhesive, and lithium is loaded in the adhesive to improve the axonal regeneration. Present data reveal that this adhesive possesses good cytocompatibility and can significantly shorten the reconnecting time of the transected nerve ends compared to that required for suture surgery. Histology, electrophysiological, and behavior assessments indicate that the adhesive reconnected nerves exhibit a low grade of fibrosis, inflammation response, and myoatrophy as well as robust axonal regeneration and functional recovery. Together, these results indicate that this octa-PEG adhesive can act as an alternative to traditional nerve suture in peripheral nerve injury.