tbuckley/cabot-search huggingface dataset:
Abstract 87: Endothelial Nogo-B Regulates Sphingolipid Biosynthesis to Promote the Onset of Pathological Hypertrophy During Chronic Pressure Overload
Authors: Yi Zhang, Yan Huang, Anna Cantalupo, Paula S Azevedo, Mauro Siragusa, Jacek Bielawski, Frank J Giordano, Annarita D Lorenzo
Journal: Circulation Research (2016)

Chronic pressure overload leads to an initial compensatory cardiac hypertrophy, and eventually to heart failure. The mechanisms regulating the transition from adaptive to pathological cardiac hypertrophy remain elusive. We recently discovered that endothelial Nogo-B, a membrane protein of the ER, regulates vascular functions by inhibiting the rate-limiting enzyme in de novo sphingolipid biosynthesis, serine palmitoyltransferase (SPT). Here, we show that sphingolipids produced by the vasculature, particularly S1P, protect the heart function during pressure overload, through a paracrine mode of action. SPT activity is upregulated in banded hearts in vivo , as well as in TNF-α-activated endothelium in vitro , and loss of Nogo-mediated brake on SPT increases the production of S1P, which enhances the coronary vasculature compliance to high pressure and endothelial barrier. Hence, mice lacking Nogo-B, systemically or specifically in the endothelium, are resistant to the onset of pathological hypertrophy. Furthermore, pharmacological inhibition of SPT with myriocin restores permeability, inflammation, and heart dysfunction in Nogo-A/B-deficient mice to wild-type levels; whereas SEW2871, an S1P 1 receptor agonist, prevents myocardial inflammation and dysfunction in WT banded mice. Our study identifies a critical role of endothelial sphingolipid biosynthesis and its regulation by Nogo-B in the development of pathological cardiac hypertrophy, and proposes a potential new therapeutic target for the attenuation or reversal of this clinical condition.
Response
Authors: Christopher G. Smith, Hannah West, Rebecca Harris, Shelley Idziaszczyk, Timothy S. Maughan, Richard Kaplan, Susan Richman, Philip Quirke, Matthew Seymour, Valentina Moskvina, Verena Steinke, Peter Propping, Frederik J. Hes, Juul Wijnen, Jeremy P. Cheadle
Journal: JNCI Journal of the National Cancer Institute (2014)
Thrombopoietin Receptor Agonists (TPO-RAs): Drug Class Considerations for Pharmacists
Authors: Jeffrey Gilreath, Mimi Lo, Joseph Bubalo
Journal: Drugs (2021)

The thrombopoietin receptor agonists (TPO-RAs) romiplostim, eltrombopag, avatrombopag, and lusutrombopag carry unique US Food and Drug Administration (US FDA)- and European Medicines Agency (EMA)-approved indications and may be used to increase platelet counts in a variety of conditions. Current indications for available TPO-RAs include treatment of chronic immune thrombocytopenia (ITP) in cases of insufficient response to prior treatment (avatrombopag, eltrombopag, romiplostim), management of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure (avatrombopag, lusutrombopag), management of severe aplastic anemia (eltrombopag), and management of thrombocytopenia associated with interferon-based therapy for hepatitis C (eltrombopag). Across current indications, pharmacists can assist in stabilizing platelet counts and help to reduce large undulations commonly seen when starting, stopping, or transitioning between these agents. If therapy modifications may benefit the patient, pharmacists should discuss possible changes with the patient's treatment team or treating physician. When used for ITP, romiplostim, eltrombopag, and avatrombopag stimulate TPO receptors on hematopoietic stem cells (also known as c-Mpl, or CD110) to promote platelet production; however, romiplostim is the only TPO-RA that binds at the same site as endogenous TPO. These subtle mechanistic differences may explain why switching TPO-RA may be clinically advantageous in some situations. As pharmacists are called to counsel patients on TPO-RA use, a deep understanding of potential adverse events and management strategies, as well as appropriate monitoring, will increase the likelihood that patients meet their goals of therapy in the shortest timeframe. Other uses of TPO-RAs are also discussed in this review, including use following hematopoietic stem cell transplant, use in myelodysplastic syndrome, and use in chemotherapy-induced thrombocytopenia.
Determination of cause of death during COVID-19 pandemic
Authors: K. M. Nada, E. Hsu, J. Seashore, M. F. Zaidan, S. P. Nishi, A. G. Duarte, G. Sharma
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Introduction: The United States has reported 13 million patients infected with SARS-CoV-2 and more than 270,000 deaths. Currently, controversy exists regarding the cause of death due to SARS-CoV-2 that is directly related to the infection or to a co-existing condition. Objective: Assess the relationship of SARS-CoV-2 infection on the cause of death in hospitalized patients. Methods: We reviewed hospital discharge summaries of patients admitted to the University of Texas Medical Branch from 3/10/2020 to 10/22/2020, with positive nasopharyngeal SARS-CoV-2 nucleic acid assay test results that expired during their hospitalization. Deidentified discharge summaries were reviewed by 2 intensivists and classified as 1) COVID-19 related, 2) COVID-19 unrelated, or 3) indeterminate. COVID-19 related cause of death was defined as a patient with acute respiratory symptoms and radiographic findings of lower respiratory tract disease requiring oxygen or mechanical ventilation. Deaths not related to COVID-19 were defined as absence of acute respiratory symptoms and radiographic findings. An indeterminate cause of death was defined as acute respiratory failure symptoms without radiographic findings. For classification disagreement, a separate group of three intensivists arbitrated to determine the cause of death. Demographics, comorbidities, prescribed medications, and ventilatory support data were collected. Comparison between COVID-19 related death group and COVID-19 unrelated death group was performed with t-test and Chi-square test. Results: We identified 15,393 patients with positive polymerase chain reaction (PCR) results for SARS-CoV-2 nucleic acid. 1052 patients were admitted within 14 days of positive test results and 100 patients expired during hospitalization. Case fatality rate was 0.65% for the total cohort and 9.5% for the hospitalized group. Hospitalized patients were predominantly male and >65 years (Table 1). Obesity (BMI>30) was present in 38% and common comorbidities were hypertension (47%), diabetes (30%) and heart failure (20%). Cause of death was classified as COVID-19 related in 85% and not COVID-19 related in 5%. The cause of death was indeterminate in 10% due to insufficient information or atypical presentation. Dexamethasone was more frequently prescribed to the COVID-related death group (p=0.0009). No differences in supplemental oxygen or mechanical ventilation were observed between groups. Length of stay was significantly greater in the COVID-19 related death group compared to the COVID-19 unrelated death group (14.21 vs 8.2 days, p=0.005). Conclusion: In hospitalized patients with SARS-CoV-2 infection, a direct cause of death was attributed to COVID- 19 in 85% of patients while an additional 10% had an atypical presentation.
Secondary sclerosing cholangitis: an emerging complication in critically ill COVID-19 patients
Authors: Philippe Meersseman, Joris Blondeel, Greet De Vlieger, Schalk van der Merwe, Diethard Monbaliu, Joost Wauters, Alexander Wilmer, Nicholas Gilbo, Ina Jochmans, Jacques Pirenne, Mauricio Sainz Barriga, Yves Debaveye, Jan Gunst, Geert Meyfroidt, Wim Laleman, Frederik Nevens, Hannah Van Malenstein, Jef Verbeek, Chris Verslype, Tania Roskams, Vincent Vandecaveye, Tim Balthazar, Christophe Vandenbriele, Greet Hermans, Peter Rogiers, Marleen Verhaegen
Journal: Intensive Care Medicine (2021)
P-265 Neoadjuvant radiotherapy for locally advanced rectal cancer during the first wave of COVID19 pandemic: Guy’s cancer cohort experience
Authors: A. Sachdeva, S. Nagpal, M. Grzeda, B. Russell, I. Petkar, A. Qureshi, M. Van Hemelrijck, P. Ross, V. Harris, K. Owczarczyk
Journal: Annals of Oncology (2021)
Reconstructing Phenotypes in Recurrent Severe Wheeze in Young Children
Authors: Jonathan M. Gaffin
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Recurrent wheeze in preschool children is troublesome for patients and providers alike.Almost half of young children wheeze by age 6 years (1) and preschool children have the highest rate of emergency department visits for asthma symptoms (2).Clinicians are often challenged to make a diagnosis, choose therapy, and discuss prognosis with families amid great heterogeneity of recurrent wheeze.Several clinical categorizations, including episodic viral wheeze (EVW) and multitrigger wheeze (MTW) (3), that reflect some combination of pattern of wheeze and similarity to childhood asthma have been used to help clinical decision-making, but fall short of truly capturing the heterogeneity of the condition (4).Fortunately, most young children with recurrent wheeze improveover time (1)or respond well to available asthma therapies (5, 6).One of the fundamental limitations to advancing our understanding of preschool wheeze is the limited access to airway samples and functional assessments of underlying lung pathophysiology in the context of the symptoms and inflammatory phenotype.Children in this age group are frequently unable to produce high-quality pulmonary function tests, and there is a high threshold for subjecting a young child to the risk of anesthesia and bronchoscopy until many medical interventions have been exhausted.Research bronchoscopy in children is unethical.In this issue of the Journal, Robinson and colleagues (pp.523-535) aimed to identify the pathophysiologic underpinnings of severe respiratory disease in young children (7).They evaluated clinical symptoms, blood inflammatory markers, allergic sensitization, and BAL samples for cytology and microbes in 105 preschool children with recurrent severe wheeze (RSW) and 31 with nonwheeze respiratory disorders (NWRD) (i.e., recurrent croup, stridor, recurrent pneumonia) presenting for clinically indicated bronchoscopy.The authors examine the phenotypic and endotypic differences between the RSW and NWRD groups, then among the RSW group, based on the European Respiratory Society-endorsed wheezing phenotypes of EVW and MTW (3).Finally, an unbiased cluster analysis segregates a combination of eight clinicopathologic features and prescription of inhaled corticosteroid therapy to create four phenotypic clusters.Surprisingly, there were no differences between neutrophils, eosinophils, or presence of bacteria in BAL samples between the RSW and NWRD groups; only blood eosinophil count was higher in the RSW group.Similarly, among children with RSW, there were no differences in lower airway pathology identified between those
SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia
Authors: Luiz H. Geraldo, Yunling Xu, Laurent Jacob, Laurence Pibouin-Fragner, Rohit Rao, Nawal Maissa, Maïté Verreault, Nolwenn Lemaire, Camille Knosp, Corinne Lesaffre, Thomas Daubon, Joost Dejaegher, Lien Solie, Justine Rudewicz, Thomas Viel, Bertrand Tavitian, Steven De Vleeschouwer, Marc Sanson, Andreas Bikfalvi, Ahmed Idbaih, Q. Richard Lu, Flavia R.S. Lima, Jean-Leon Thomas, Anne Eichmann, Thomas Mathivet
Journal: Journal of Clinical Investigation (2021)

SLIT2 is a secreted polypeptide that guides migration of cells expressing Roundabout 1 and 2 (ROBO1 and ROBO2) receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1- and ROBO2-mediated PI3K-γ activation. Macrophage Robo1 and Robo2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors.
Abstract 34: Human Cardiac Mesenchymal Cell Derived Extracellular Vesicles Promote Angiogenesis Through Angiopoietin-TIE2 Signaling
Authors: Asif Pathan, Talha Farid, Abdur Rahman Khan, Marjan Nasr, Marcin Wysoczynski, Roberto Bolli
Journal: Circulation Research (2016)

Cell-based therapy is considered a promising approach to treat the damaged heart due to myocardial infarction. Although the mechanisms for their beneficial action are not yet clear, exosome/extracellular vesicles (EVs) secreted by these cells may be involved in their reparative paracrine signaling. Previous studies have suggested that EVs isolated from several cell types (e.g. cardiosphere-derived cells, embryonic stem cell, CD34+ stem cells) induce angiogenic activity both in vitro and in vivo . Here, we investigated whether EVs secreted by adult human cardiac mesenchymal cells (hCMCs) exhibit pro-angiogenic activity, and if so, what signaling molecules are involved in this process. hCMCs were isolated from right atrial appendage of patients undergoing cardiac procedures and were characterized by the expression of classical mesenchymal markers- CD29 (99.1%), CD73 (99.0%), CD90 (20.4%), CD105 (99.3%), CD 31 (16.8%), CD34 (0.9%) and CD45 (0.1%). EVs isolated from serum-free 24-hour hCMC conditioned media using PEG4000-based precipitation technique exhibited two distinct population of particles with size range of 10-60nm and 100-500nm in diameter; expressed characteristic exosomal markers- CD63, HSP70, Flotillin-1 and were negative for cellular organelle markers- calreticulin (ER and apoptotic bodies), prohibitin (mitochondria), GM130 (Golgi), Lamin B (nuclear protein), β-actin (cytoskeleton) and PMP70 (peroxisomes) as determined by immunoblotting. In vitro assays revealed that hCMC EVs promote human umbilical cord endothelial cells (HUVECs) proliferation, transwell migration in Boyden chamber and tube formation on Matrigel, indicative of enhanced angiogenesis. Angiogenic proteomic array identified that angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) proteins are highly enriched in EVs secreted by hCMCs. Furthermore, hCMC EV mediated HUVEC migration and tube formation was inhibited by TIE2 kinase inhibitor. Overall, these findings suggest that ANG-1 and ANG-2 are the key component of hCMC secreted EVs and they promote angiogenesis by activating TIE2 receptor in endothelial cells.
SETD7-mediated monomethylation is enriched on soluble Tau in Alzheimer’s disease
Authors: Maria Bichmann, Nuria Prat Oriol, Ebru Ercan-Herbst, David C. Schöndorf, Borja Gomez Ramos, Vera Schwärzler, Marie Neu, Annabelle Schlüter, Xue Wang, Liang Jin, Chenqi Hu, Yu Tian, Janina S. Ried, Per Haberkant, Laura Gasparini, Dagmar E. Ehrnhoefer
Journal: Molecular Neurodegeneration (2021)

Abstract Background Human tauopathies including Alzheimer’s disease (AD) are characterized by alterations in the post-translational modification (PTM) pattern of Tau, which parallel the formation of insoluble Tau aggregates, neuronal dysfunction and degeneration. While PTMs on aggregated Tau have been studied in detail, much less is known about the modification patterns of soluble Tau. Furthermore, PTMs other than phosphorylation have only come into focus recently and are still understudied. Soluble Tau species are likely responsible for the spreading of pathology during disease progression and are currently being investigated as targets for immunotherapies. A better understanding of their biochemical properties is thus of high importance. Methods We used a mass spectrometry approach to characterize Tau PTMs on a detergent-soluble fraction of human AD and control brain tissue, which led to the discovery of novel lysine methylation events. We developed specific antibodies against Tau methylated at these sites and biochemically characterized methylated Tau species in extracts from human brain, the rTg4510 mouse model and in hiPSC-derived neurons. Results Our study demonstrates that methylated Tau levels increase with Tau pathology stage in human AD samples as well as in a mouse model of Tauopathy. Methylated Tau is enriched in soluble brain extracts and is not associated with hyperphosphorylated, high molecular weight Tau species. We also show that in hiPSC-derived neurons and mouse brain, methylated Tau preferentially localizes to the cell soma and nuclear fractions and is absent from neurites. Knock down and inhibitor studies supported by proteomics data led to the identification of SETD7 as a novel lysine methyltransferase for Tau. SETD7 specifically methylates Tau at K132, an event that facilitates subsequent methylation at K130. Conclusions Our findings indicate that methylated Tau has a specific somatic and nuclear localization, suggesting that the methylation of soluble Tau species may provide a signal for their translocation to different subcellular compartments. Since the mislocalization and depletion of Tau from axons is associated with tauopathies, our findings may shed light onto this disease-associated phenomenon.
Interleukin-6 and intrapulmonary shunt
Authors: Francisco Perez-Vizcaino, Laura Moreno, José A. Lorente
Journal: European Respiratory Journal (2021)

We read with interest the article by Kotwica et al. [1] showing the utility of clinical pulse oximetry measurements to quantify shunt and ventilation–perfusion mismatch and their predictive value in severe coronavirus disease 2019 (COVID-19). The authors found that shunt correlated with markers of activated inflammatory response ( i.e. C-reactive protein) but not those of activated coagulation (such as D-dimer). Their results reinforce the growing evidence for the role of impaired hypoxic pulmonary vasoconstriction (HPV) as a primary cause for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced hypoxaemia [2]. Based on animal studies and indirect clinical evidence, it may be speculated that IL-6 has a pathophysiological role in intrapulmonary shunt associated to COVID-19 <https://bit.ly/3whQVqd>
Focused ultrasound with anti-pGlu3 Aβ enhances efficacy in Alzheimer's disease-like mice via recruitment of peripheral immune cells
Authors: Tao Sun, Qiaoqiao Shi, Yongzhi Zhang, Chanikarn Power, Camilla Hoesch, Shawna Antonelli, Maren K. Schroeder, Barbara J. Caldarone, Nadine Taudte, Mathias Schenk, Thore Hettmann, Stephan Schilling, Nathan J. McDannold, Cynthia A. Lemere
Journal: Journal of Controlled Release (2021)
Abstract 98: Profiling GPCR Expression in Cardiac Fibroblasts and Myofibroblasts
Authors: Krishna Sriram, Nakon Aroonsakool, Alexander Michkov, Paul Insel
Journal: Circulation Research (2016)

G-protein coupled receptors (GPCRs) are the largest class of cell surface receptors, serving as drug targets, at least in part, due to their diversity, selectivity in tissue expression and ability to regulate a wide variety of cellular functions. We hypothesized that cardiac fibroblasts (CFs) and pro-fibrotic myofibroblasts (myoFs) may express GPCRs that will regulate their activity and will identify previously unappreciated GPCRs as potential therapeutic targets for cardiac fibrosis. To test this hypothesis, we profiled non-chemosensory GPCR mRNA expression by using qPCR-based GPCR arrays in studies of CFs isolated from ventricular tissue of rats, mice and humans. Particular attention was paid to assessing cells at low passage (1-3) and grown on substrates that mimic the stiffness of cardiac tissue in-vivo. MyoFs were obtained by treating CFs ex-vivo with TGFβ, and from CFs that spontaneously transformed to MyoFs by growth on hard tissue culture substrates.We find that CFs from humans, rats and mice express ~120 GPCRs and that a majority of GPCRs (&gt;75%), especially highly expressed GPCRs, are detected in human, rats and/or mice CFs; ~40% of highly expressed GPCRs are orphan receptors (without known physiologic agonists). Of GPCRs with known G-protein linkages, Gi-coupled receptors are most numerous, followed by Gq-, Gs- and G12/13-coupled GPCRs. GPCR expression profiles of rat atrial and ventricular CFs are highly similar in terms of both identity and level of expression. By contrast, GPCR expression in cardiac myocytes (CMs) differs significantly from CFs: most highly expressed receptors in CFs are undetected or much lower expressed in CMs. Several GPCRs detected in MyoFs have reduced expression vs CFs but a subset of GPCRs have higher expression in MyoFs. Validation of mRNA expression via protein detection as well as functional assays helps confirm the presence of a large number of the GPCRs. Conclusions: CFs and MyoFs from rodents and humans express ~120 GPCRs, including many orphan GPCRs. Atrial and ventricular CFs have similar GPCR profiles but ones that differ from that of CMs. CFs and MyoFs show differences in the number and nature of GPCRs expressed. We hypothesize that GPCRs higher expressed in MyoFs may contribute to their pro-fibrotic phenotype.
Post‐discharge arrhythmic risk stratification of patients with acute myocarditis and life‐threatening ventricular tachyarrhythmias
Authors: Piero Gentile, Marco Merlo, Giovanni Peretto, Enrico Ammirati, Simone Sala, Paolo Della Bella, Giovanni Donato Aquaro, Massimo Imazio, Luciano Potena, Jeness Campodonico, Alberto Foà, Anne Raafs, Mark Hazebroek, Michela Brambatti, Andreja Cerne Cercek, Gaetano Nucifora, Sanskriti Shrivastava, Florent Huang, Matthieu Schmidt, Daniele Muser, Caroline M. Van de Heyning, Emeline Van Craenenbroeck, Tatsuo Aoki, Koichiro Sugimura, Hiroaki Shimokawa, Antonio Cannatà, Jessica Artico, Aldostefano Porcari, Marzia Colopi, Andrea Perkan, Rossana Bussani, Giulia Barbati, Andrea Garascia, Manlio Cipriani, Piergiuseppe Agostoni, Naveen Pereira, Stephane Heymans, Eric D. Adler, Paolo Guido Camici, Maria Frigerio, Gianfranco Sinagra
Journal: European Journal of Heart Failure (2021)
Screening strategies for identifying RNA- and ribonucleoprotein-targeted compounds
Authors: William J. Martin, Paola Grandi, Marco Marcia
Journal: Trends in Pharmacological Sciences (2021)

The past few years have witnessed important breakthroughs in the identification of compounds that specifically bind and regulate RNAs and in optimizing them for therapeutic use. Here, we review successful and unsuccessful approaches in screening for RNA-targeted small molecules. We discuss advantages and disadvantages of the different screening techniques and variables that affect the outcome of RNA-screening projects. We also highlight key challenges that hamper the development of quality RNA ligands, especially the still-low availability of RNA-specific compound libraries and the poor understanding of RNA structural dynamics. We conclude that the development of new RNA-targeting drugs would greatly benefit from integration of the power of high-throughput screening technologies with improved biochemical, structural, and computational characterization of RNA targets.
Abstract 10401: Human Immunodeficiency Virus Infection and Risks of Death and Heart Failure Hospitalization in Adults With Incident Heart Failure
Authors: Harshith R Avula, Andrew P Ambrosy, Michael J Silverberg, Kristi Reynolds, William J Towner, Rulin C Hechter, Michael Horberg, Suma Vupputuri, Thomas K Leong, Wendy A Leyden, Teresa N Harrison, Keane K Lee, Sue Hee Sung, Alan S Go
Journal: Circulation (2019)

Introduction: People living with HIV (PLWH) are at increased risk of incident heart failure (HF), but whether HIV status independently influences HF-related morbidity and mortality is unclear. Meth...