tbuckley/cabot-search huggingface dataset:
Bilateral Peritoneoscrotal Communication—“Chicken Leg” Appearance Demonstrated on 99mTc–Sulfur Colloid Scintigraphy
Authors: Tanigassalam Sindhu, Anwin Joseph Kavanal, Harish Goyal, Bhagwant Rai Mittal, Anish Bhattacharya
Journal: Clinical Nuclear Medicine (2020)

Abstract Continuous ambulatory peritoneal dialysis is a convenient alternate form of treatment in patients receiving hemodialysis for renal failure. Sometimes during the procedure, patients may develop scrotal swelling because of patent processus vaginalis. The diagnostic utility of the peritoneal scintigraphy, an infrequently performed nuclear medicine scan to identify peritoneoscrotal communication, has been reported by many authors. Most of the previous case reports in the literature demonstrated unilateral peritoneoscrotal communication. We present an interesting 99m Tc–sulfur colloid peritoneal scintigraphic image finding of bilateral peritoneoscrotal communication in a 67-year-old man who developed scrotal swelling while undergoing continuous ambulatory peritoneal dialysis.
Inflammation in Glaucoma: From the back to the front of the eye, and beyond
Authors: Christophe Baudouin, Miriam Kolko, Stéphane Melik-Parsadaniantz, Elisabeth M. Messmer
Journal: Progress in Retinal and Eye Research (2020)

The pathophysiology of glaucoma is complex, multifactorial and not completely understood. Elevated intraocular pressure (IOP) and/or impaired retinal blood flow may cause initial optic nerve damage. In addition, age-related oxidative stress in the retina concurrently with chronic mechanical and vascular stress is crucial for the initiation of retinal neurodegeneration. Oxidative stress is closely related to cell senescence, mitochondrial dysfunction, excitotoxicity, and neuroinflammation, which are involved in glaucoma progression. Accumulating evidence from animal glaucoma models and from human ocular samples suggests a dysfunction of the para-inflammation in the retinal ganglion cell layer and the optic nerve head. Moreover, quite similar mechanisms in the anterior chamber could explain the trabecular meshwork dysfunction and the elevated IOP in primary open-angle glaucoma. On the other hand, ocular surface disease due to topical interventions is the most prominent and visible consequence of inflammation in glaucoma, with a negative impact on filtering surgery failure, topical treatment efficacy, and possibly on inflammation in the anterior segment. Consequently, glaucoma appears as an outstanding eye disease where inflammatory changes may be present to various extents and consequences along the eye structure, from the ocular surface to the posterior segment, and the visual pathway. Here we reviewed the inflammatory processes in all ocular structures in glaucoma from the back to the front of the eye and beyond. Our approach was to explain how para-inflammation is necessary to maintain homoeostasis, and to describe abnormal inflammatory findings observed in glaucomatous patients or in animal glaucoma models, supporting the hypothesis of a dysregulation of the inflammatory balance toward a pro-inflammatory phenotype. Possible anti-inflammatory therapeutic approaches in glaucoma are also discussed.
Silver Lining: Reduced Relapse with Chronic GVHD after Transplant for MDS
Authors: Ashley M. Eckel, H. Joachim Deeg
Journal: Clinical Cancer Research (2020)

Chronic GVHD following hematopoietic cell transplantation is associated with reduced relapse incidence in patients with leukemias. This impact has been investigated in myelodysplastic syndrome, showing a beneficial impact of limited chronic GVHD on transplant outcomes in a cohort of more than 3,000 patients.See related article by Konuma et al., p. 6483.
Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes
Authors: Daniel E Leisman, Lukas Ronner, Rachel Pinotti, Matthew D Taylor, Pratik Sinha, Carolyn S Calfee, Alexandre V Hirayama, Fiore Mastroiani, Cameron J Turtle, Michael O Harhay, Matthieu Legrand, Clifford S Deutschman
Journal: The Lancet Respiratory Medicine (2020)
Reawakening of Human Fetal Hemoglobin and an Epigenetic Path to the Clinic for Sickle Cell Disease and Beta-Thalassemia: Identification of an Orally-Available, Potent, and Selective Euchromatic Histone Lysine Methyltransferase 1 and 2 (EHMT1/2) Inhibitor
Authors: Elayne Chan-Penebre, Veronica Gibaja, John Campbell, Ogunbodede Olu, Elizabeth Admirand, Dorothy Brach, Cuyue Tang, Alejandra Raimondi, Tami Hood, Alexis Cocozaki, Sule Karaman, Kimberly Stickland, Christopher Plescia, Michael Munchhof, Kelli Armstrong, Thomas Riera, Stuart Orkin, Ann Boriack-Sjodin, William Janzen, Stephen Blakemore, Scott A Ribich, Richard Chesworth, Jesse J Smith, Kenneth W Duncan
Journal: Blood (2017)
Evolving treatment patterns and outcomes in older patients (≥60 years) with AML: changing everything to change nothing?
Authors: David Martínez-Cuadrón, Josefina Serrano, Cristina Gil, Mar Tormo, Pilar Martínez-Sánchez, José A. Pérez-Simón, Raimundo García-Boyero, Carlos Rodríguez-Medina, María López-Pavía, Celina Benavente, Juan Bergua, Esperanza Lavilla-Rubira, María L. Amigo, Pilar Herrera, Juan M. Alonso-Domínguez, Teresa Bernal, Mercedes Colorado, María J. Sayas, Lorenzo Algarra, María B. Vidriales, Gabriela Rodríguez-Macías, Susana Vives, Manuel M. Pérez-Encinas, Aurelio López, Víctor Noriega, María García-Fortes, Fernando Ramos, Juan I. Rodríguez-Gutiérrez, Lisette Costilla-Barriga, Jorge Labrador, Blanca Boluda, Rebeca Rodríguez-Veiga, Joaquín Martínez-López, Miguel A. Sanz, Pau Montesinos
Journal: Leukemia (2020)
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial
Authors: Andrew Tutt, Mark Robson, Judy E Garber, Susan M Domchek, M William Audeh, Jeffrey N Weitzel, Michael Friedlander, Banu Arun, Niklas Loman, Rita K Schmutzler, Andrew Wardley, Gillian Mitchell, Helena Earl, Mark Wickens, James Carmichael
Journal: The Lancet (2010)
Functional α6β4 acetylcholine receptor expression enables pharmacological testing of nicotinic agonists with analgesic properties
Authors: Daniel Knowland, Shenyan Gu, William A. Eckert, G. Brent Dawe, Jose A. Matta, James Limberis, Alan D. Wickenden, Anindya Bhattacharya, David S. Bredt
Journal: Journal of Clinical Investigation (2020)

The α6β4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP's N-terminal region and IRE1α's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.
Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis
Authors: Fanxun Zeng, Shiliang Li, Guantian Yang, Yating Luo, Tiantian Qi, Yingfan Liang, Tingyuan Yang, Letian Zhang, Rui Wang, Lili Zhu, Honglin Li, Xiaoyong Xu
Journal: Acta Pharmaceutica Sinica B (2020)

Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure–activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53‒55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.
Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia
Authors: Begüm Alankus, Veronika Ecker, Nathalie Vahl, Martina Braun, Wilko Weichert, Stephan Macher-Göppinger, Torben Gehring, Tanja Neumayer, Thorsten Zenz, Maike Buchner, Jürgen Ruland
Journal: The Journal of Experimental Medicine (2020)

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell–intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma–derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus–like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL–RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell–intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.
Retraction notice to Gadolinium-Free Cardiac MR Stress T1-Mapping to Distinguish Epicardial From Microvascular Coronary Disease
Authors: Alexander Liu, Rohan S. Wijesurendra, Joanna M. Liu, Andreas Greiser, Michael Jerosch-Herold, John C. Forfar, Keith M. Channon, Stefan K. Piechnik, Stefan Neubauer, Rajesh K. Kharbanda, Vanessa M. Ferreira
Journal: Journal of the American College of Cardiology (2020)

This article has been retracted: please see Elsevier Policy on Article Withdrawal ( ).

The JACC Journals Ethics Board has voted to retract this paper, relying on the findings of misconduct after an investigation by the
Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
Authors: Lindsey T. Brinton, Pu Zhang, Katie Williams, Daniel Canfield, Shelley Orwick, Steven Sher, Ronni Wasmuth, Larry Beaver, Casey Cempre, Jordan Skinner, Matthew Cannon, Mukul Govande, Bonnie Harrington, Amy Lehman, John C. Byrd, Rosa Lapalombella, James S. Blachly
Journal: Journal of Hematology & Oncology (2020)

Abstract Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 ( FLT3 -ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3 -ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding.
Integrative analysis for COVID-19 patient outcome prediction
Authors: Hanqing Chao, Xi Fang, Jiajin Zhang, Fatemeh Homayounieh, Chiara D. Arru, Subba R. Digumarthy, Rosa Babaei, Hadi K. Mobin, Iman Mohseni, Luca Saba, Alessandro Carriero, Zeno Falaschi, Alessio Pasche, Ge Wang, Mannudeep K. Kalra, Pingkun Yan
Journal: Medical Image Analysis (2020)
Deep pyramid local attention neural network for cardiac structure segmentation in two-dimensional echocardiography
Authors: Fei Liu, Kun Wang, Dan Liu, Xin Yang, Jie Tian
Journal: Medical Image Analysis (2020)

Automatic semantic segmentation in 2D echocardiography is vital in clinical practice for assessing various cardiac functions and improving the diagnosis of cardiac diseases. However, two distinct problems have persisted in automatic segmentation in 2D echocardiography, namely the lack of an effective feature enhancement approach for contextual feature capture and lack of label coherence in category prediction for individual pixels. Therefore, in this study, we propose a deep learning model, called deep pyramid local attention neural network (PLANet), to improve the segmentation performance of automatic methods in 2D echocardiography. Specifically, we propose a pyramid local attention module to enhance features by capturing supporting information within compact and sparse neighboring contexts. We also propose a label coherence learning mechanism to promote prediction consistency for pixels and their neighbors by guiding the learning with explicit supervision signals. The proposed PLANet was extensively evaluated on the dataset of cardiac acquisitions for multi-structure ultrasound segmentation (CAMUS) and sub-EchoNet-Dynamic, which are two large-scale and public 2D echocardiography datasets. The experimental results show that PLANet performs better than traditional and deep learning-based segmentation methods on geometrical and clinical metrics. Moreover, PLANet can complete the segmentation of heart structures in 2D echocardiography in real time, indicating a potential to assist cardiologists accurately and efficiently.
Correction to: Preliminary evaluation of the Vision PERformance (VIPER) simulator
Authors: Denise S. Ryan, Rose K. Sia, Jennifer B. Eaddy, Lorie A. Logan, Jide O. Familoni, Hind Beydoun, Samantha B. Rodgers, Bruce A. Rivers
Journal: Military Medical Research (2020)

An amendment to this paper has been published and can be accessed via the original article.
A discrete subset of epigenetically primed human NK cells mediates antigen-specific immune responses
Authors: Victoria Stary, Ram Vinay Pandey, Johanna Strobl, Lisa Kleissl, Patrick Starlinger, David Pereyra, Wolfgang Weninger, Gottfried F. Fischer, Christoph Bock, Matthias Farlik, Georg Stary
Journal: Science Immunology (2020)

Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49a+CD16- NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16- NK cells when compared with conventional CD49a-CD16+ NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a+CD16- NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.
Defining and Classifying New Subgroups of Diabetes
Authors: Ashok Balasubramanyam
Journal: Annual Review of Medicine (2020)

An etiologically based classification of diabetes is needed to account for the heterogeneity of type 1 and type 2 diabetes (T1D and T2D) and emerging forms of diabetes worldwide. It may be productive for both classification and clinical discovery to consider variant forms of diabetes as a spectrum. Maturity onset diabetes of youth and neonatal diabetes serve as models for etiologically defined, rare forms of diabetes in the spectrum. Ketosis-prone diabetes is a model for more complex forms, amenable to phenotypic dissection. Bioinformatic approaches such as clustering analyses of large datasets and multi-omics investigations of rare and atypical phenotypes are promising avenues to explore and define new subgroups of diabetes.
AB0068 NOVEL ANTI-ANGIOGENIC EFFECTS OF TOFACITINIB IN FIBROBLAST-LIKE SYNOVIOCYTES DERIVED FROM PATIENTS WITH RA
Authors: Yohei Kawaguchi, Yuko Waguri-Nagaya, Yuji Joyo, Yusuke Oguri, Masahiro Nozaki, Kiyofumi Asai
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Angiogenesis, which is the growth of new capillaries from pre-existing blood vessels, is an essential pathological feature of rheumatoid arthritis (RA). Gliostatin (GLS) is known to have angiogenic activity and thymidine phosphorylase activity. We have previously demonstrated that the production of GLS was enhanced by TNF-α and GLS induced vascular endothelial growth factor (VEGF) expression in fibroblast-like synoviocytes derived from patients with RA (RA-FLSs) [1]. The JAK/STAT signaling pathways mediate the effects of many cytokines and growth factors related RA. Tofacitinib is a novel oral JAK inhibitor and it has demonstrated high efficacy in RA, even in non-responder to anti-TNF treatment [2]. However it have been reported that RA-FLSs with the treatment of tofacitinib suppress the production of chemokines, IL-6 and granulocyte colony-stimulating factor [3, 4], the anti-angiogenic effects of tofacitinib remain to been elucidated. <h3>Objectives:</h3> The purpose of this study was to investigate the suppression of angiogenic factors such as VEGF, tenascin-C (TNC) and GLS in RA-FLSs treated with tofacitinib. <h3>Methods:</h3> RA-FLSs were stimulated by TNF-α with or without pre-treatment of tofacitinib. The expression levels of VEGF, TNC and GLS were determined using reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). <h3>Results:</h3> In cultured RA-FLSs, VEGF, TNC and GLS were significantly induced by stimulation with TNF-α alone and these inductions were significantly suppressed by treatment of tofacitinib in a dose-dependent manner. <h3>Conclusion:</h3> These findings indicate tofacitinib inhibits the VEGF, TNC and GLS production through blockade of a JAK/STAT pathway. Tofacitinib may extinguish inflammatory synovitis through preventing excessive angiogenic factors in RA-FLSs. <h3>References</h3> [1] Tanikawa T, et al. Gliostatin/thymidine phosphorylase-regulated vascular endothelial growth-factor production in human fibroblast-like synoviocytes. Rheumatol Int2007; 27:553-559. [2] Kawaguchi Y, et al. The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes. Clin Exp Rheumatol2018;36:559-567. [3] Migita K, et al. CP690,550 inhibits oncostatin M-induced JAK/STAT signaling pathway in rheumatoid synoviocytes. Arthritis Res Ther2011;13:R72. [4] Rosengren S, et al. The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis2012;71:440-447. <h3>Acknowledgement:</h3> This research was supported by Grand-in-Aid for Scientific Research (C) (26462309) and 16K10913 from the Japan Society for the Promotion of Science. <h3>Disclosure of Interests:</h3> None declared
CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells
Authors: Matthias Braun, Amelia Roman Aguilera, Ashmitha Sundarrajan, Dillon Corvino, Kimberley Stannard, Sophie Krumeich, Indrajit Das, Luize G. Lima, Lizeth G. Meza Guzman, Kunlun Li, Rui Li, Nazhifah Salim, Maria Villancanas Jorge, Sunyoung Ham, Gabrielle Kelly, Frank Vari, Ailin Lepletier, Ashwini Raghavendra, Sally Pearson, Jason Madore, Sebastien Jacquelin, Maike Effern, Brodie Quine, Lambros T. Koufariotis, Mika Casey, Kyohei Nakamura, Eun Y. Seo, Michael Hölzel, Matthias Geyer, Glen Kristiansen, Touraj Taheri, Elizabeth Ahern, Brett G.M. Hughes, James S. Wilmott, Georgina V. Long, Richard A. Scolyer, Martin D. Batstone, Jennifer Landsberg, Dimo Dietrich, Oltin T. Pop, Lukas Flatz, William C. Dougall, André Veillette, Sandra E. Nicholson, Andreas Möller, Robert J. Johnston, Ludovic Martinet, Mark J. Smyth, Tobias Bald
Journal: Immunity (2020)
DUX4 Transcript Knockdown with Antisense 2′-O-Methoxyethyl Gapmers for the Treatment of Facioscapulohumeral Muscular Dystrophy
Authors: Kenji Rowel Q. Lim, Adam Bittel, Rika Maruyama, Yusuke Echigoya, Quynh Nguyen, Yiqing Huang, Kasia Dzierlega, Aiping Zhang, Yi-Wen Chen, Toshifumi Yokota
Journal: Molecular Therapy (2020)

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by a progressive, asymmetric weakening of muscles, starting with those in the upper body. It is caused by aberrant expression of the double homeobox protein 4 gene (DUX4) in skeletal muscle. FSHD is currently incurable. We propose to develop a therapy for FSHD using antisense 2′-O-methoxyethyl (2′-MOE) gapmers, to knock down DUX4 mRNA expression. Using immortalized patient-derived muscle cells and local intramuscular injections in the FLExDUX4 FSHD mouse model, we showed that our designed 2′-MOE gapmers significantly reduced DUX4 transcript levels in vitro and in vivo, respectively. Furthermore, in vitro, we observed significantly reduced expression of DUX4-activated downstream targets, restoration of FSHD signature genes by RNA sequencing, significant improvements in myotube morphology, and minimal off-target activity. This work facilitates the development of a promising candidate therapy for FSHD and lays down the foundation for in vivo systemic treatment studies. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by a progressive, asymmetric weakening of muscles, starting with those in the upper body. It is caused by aberrant expression of the double homeobox protein 4 gene (DUX4) in skeletal muscle. FSHD is currently incurable. We propose to develop a therapy for FSHD using antisense 2′-O-methoxyethyl (2′-MOE) gapmers, to knock down DUX4 mRNA expression. Using immortalized patient-derived muscle cells and local intramuscular injections in the FLExDUX4 FSHD mouse model, we showed that our designed 2′-MOE gapmers significantly reduced DUX4 transcript levels in vitro and in vivo, respectively. Furthermore, in vitro, we observed significantly reduced expression of DUX4-activated downstream targets, restoration of FSHD signature genes by RNA sequencing, significant improvements in myotube morphology, and minimal off-target activity. This work facilitates the development of a promising candidate therapy for FSHD and lays down the foundation for in vivo systemic treatment studies.