tbuckley/cabot-search huggingface dataset:
Abstract 814: Trpv4 Deletion in Endothelium Protects Heart Against Pressure Overload Induced Hypertrophy
Authors: Ravi K Adapala, Anantha K Kanugula, Vahagn Ohanyan, Nina Lenkey, Sailaja Paruchuri, William M Chilian, Charles K Thodeti
Journal: Circulation Research (2019)

Coronary microvascular dysfunction has been identified as one of the underlying causes for progression of heart failure following hypertrophy or myocardial infarction. However, the mechanisms underlying microvascular dysfunction during the progression of heart failure are unknown. Recently, we found that transient receptor potential vanilloid 4 (TRPV4) channel acts as mechanosensor in endothelial cells and negatively regulates angiogenesis. Therefore, to determine the role of TRPV4 in coronary microvascular function during pathological hypertrophy, we have induced pressure-overload in WT and TRPV4KO mice via transverse aortic constriction (TAC). We found that TAC-induced cardiomyocyte hypertrophy and reduced cardiac function in WT mice, after 28 days. In contrast, both myocyte structure and cardiac function were preserved in TRPV4KO-TAC compared to WT-TAC mice. Notably, WT-TAC hearts exhibited increased ECM deposition and reduced microvascular density compared to TRPV4KO-TAC hearts, suggesting that the absence of TRPV4 may protect myocardium from pressure-overload-induced stress. To evaluate the specific role of endothelial TRPV4 in coronary microvascular function, endothelial specific TRPV4KO (TRPV4 ECKO ) mice were generated by crossing TRPV4 lox/lox mice with Tie2-Cre mice. After confirming endothelial deletion of TRPV4 through RT-PCR and immunostaining, we have subjected TRPV4 lox/lox and TRPV4 ECKO mice to TAC. Immuno-histological analysis revealed that TRPV4 ECKO hearts exhibited increased microvascular density compared to TRPV4 lox/lox mice, 28 days post TAC. Further, we found preserved cardiac structure (myocyte cross sectional area) and cardiac function (% ejection fraction and fractional shortening) with reduced cardiac fibrosis in TRPV4 ECKO mice compared to TRPV4 lox/lox , post TAC. Thus, our results suggest that endothelial TRPV4 channels are key regulators of coronary microvasculature function and deletion of endothelial TRPV4 offers cardio-protection via increased coronary angiogenesis following pressure overload-induced by TAC.
Analysis of Genetic Abnormalities in Newly Diagnosed Acute Lymphoblastic Leukemia Patients at King Faisal Specialist Hospital &amp; Research Centre
Authors: Osamah Khojah, Mohammed Almajed, Shahad Fareed Barri, Ahmed Alfaran, Mohammed Alsharif, Nasser Alsaif, Abdulaziz Alrajeh, Suleimman Al-Sweedan, Salem Khalil
Journal: Blood (2018)
Abstract 931: Compensatory Response of Perivascular Adipose Tissue to Vascular Dysfunction in Metabolic Syndrome Rats Involves Apelin
Authors: Satomi Kagota, Miho Shimari, Kana Maruyama-Fumoto, Saki Iwata, Kazumasa Shinozuka
Journal: Circulation Research (2019)

Perivascular adipose tissue (PVAT) regulates vascular homeostasis including vascular tone via release of adipokines. Using SHRSP.Z- Lepr fa /IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS), we have demonstrated that mesenteric PVAT enhances vasodilation under impaired vasodilation, in response to nitric oxide. We have also shown that the compensatory effect of PVAT disappears later in the course of MetS. Apelin is an adipokine that is produced at high levels in obesity and acts as a vasorelaxing factor. In this study, we evaluated the role of apelin in the enhancing effect of mesenteric PVAT on relaxations in SHRSP.ZF rats, by examining whether apelin canenhance vasorelaxation in the mesenteric arteries of SHRSP.ZF rats without PVAT, as it does in those with PVAT. Furthermore, we investigated whether apelin expression changes with increasing age. SHRSP.ZF rats at 17, 20, 23, and 30 weeks old were used. The mesenteric artery and surrounding adipose tissue were isolated from each rat; PVAT samples were isolated from surrounding adipose tissue; and the mRNA transcript level of apelin was examined by quantitative real-time PCR assays. Mesenteric arterial ring preparations with and without PVAT were made, and after a stable contraction was obtained by adding phenylephrine, relaxation was elicited using acetylcholine in the presence or absence of apelin (100 ng/mL, 20 min). There was no significant difference in apelin mRNA levels between 17 and 20 weeks, but there was a decrease at 23 and 30 weeks of age, which was when the enhancing effect of PVAT on vasodilation in SHRSP.ZF rats was impaired. In the presence of apelin, acetylcholine-induced relaxation in arteries without PVAT was significantly increased to the level of the response in arteries with PVAT in SHRSP.ZF rats at 20 weeks. These findings suggest that apelin is involved in the enhancing effect of PVAT in MetS rat mesenteric artery, and decreases in the level is associated with deterioration of PVAT function. Further study to investigate the mechanisms underlying the decrease in apelin production with increasing age in metabolic syndrome is needed, butthe apelin level could be one of the predictors for development of cardiovascular complications in patients with MetS.
Gut-derived CD8<sup>+</sup> tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients
Authors: Giuliana Guggino, Aroldo Rizzo, Daniele Mauro, Federica Macaluso, Francesco Ciccia
Journal: Annals of the Rheumatic Diseases (2019)

We read with interest the recently published paper from Qaiyum et al 1 demonstrating a novel integrin-expressing mature Crohn's disease (CD)8+ T cell population defined as CD49a+CD103+β7+CD29+ cells in the synovial fluids of ankylosing spondylitis (AS) patients. Although the authors did not analyse gut samples from AS patients, they speculate that these cells might be gut-derived cells. Interestingly, as stated by authors, the transcriptional and phenotypic signature of these cells is reminiscent of human tissue-resident memory T cells (TRM). TRM are a subset of cells important as the first line of defence from infection in mucosal tissues, never studied in spondyloarthritis (SpA).2 For clarifying whether these cells could be of intestinal original, we set up additional analyses, wondering if we could see similar results in paired samples of patients with SpA.

Paired gut and synovial samples and fluids and peripheral blood samples (PCMCs) were obtained from patients with SpA (HLA-B27 positive; n=6), …
The Prediction of Clinical Outcome By Controlling Nutrition Status (CONUT) before Allogeneic Hematopoietic Stem Cell Transplantation in Myeloid Malignancies
Authors: Hiroaki Araie, Tomoe Ichiki, Motohito Okabe, Yuka Kawaguchi, Yoonha Lee, Marie Ohbiki, Masahide Osaki, Miyo Goto, Takahiko Sato, Tatsunori Goto, Takanobu Morishita, Yukiyasu Ozawa, Koichi Miyamura
Journal: Blood (2018)
Alterations in the Properties of MSCs in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) without Bone Marrow Involvement
Authors: Ekaterina Fastova, Aminat U. Magomedova, Nataliya Petinati, Natalia Sats, Nina Drize, Nikolay M. Kapranov, Julia Davydova, Irina Malyants, Viktoria Shendler, Georgiy Arapidi, Maria Lagarkova, Sergey K. Kravchenko, Valeriy G. Savchenko
Journal: Blood (2018)
Abstract 805: A Toll-like Receptor 9 Inhibitor Prevents the Development and Progression of Sterile Inflammatory Heart Failure Induced by Mitochondrial DNA Accumulation
Authors: Hiromichi Ueda, Manabu Taneike, Kinya Otsu, Yasushi Sakata
Journal: Circulation Research (2019)

Mitochondrial DNA contains unmethylated cytidine-phosphate-guanosine motif, and is recognized by Toll-like receptor (TLR) 9, inducing sterile inflammation. We previously reported that the accumulation of mitochondrial DNA in cardiomyocytes induces myocardial inflammation and heart failure using an animal model. (Nature 2012) In this study, to investigate the effect of inhibition of the inflammation via TLR9 induced by mitochondrial DNA accumulation on heart failure, we examined whether a TLR9 inhibitor, E6446 (6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole), prevents the development and progression of heart failure in mice. In in vitro study, isolated cardiomyocytes were stimulated by a TLR9 ligand (ODN1668) in the presence of E6446. ODN1668 significantly increased the expression levels of inflammatory cytokine mRNAs in the cells. Incubation of cardiomyocytes with E6446 significantly reduced the level of those mRNAs induced by ODN1668. CCCP increased the number of autolysosomes with DNA accumulation. Although E6446 had no effect on the number of the autolysosomes, it significantly reduced the production of inflammatory cytokine mRNAs induced by CCCP in cardiomyocytes. In in vivo study, mice orally received E6446 or saline 2 days before transverse aortic constriction (TAC) and every two days for 4 weeks thereafter. Four weeks after TAC, chamber size and fractional shortening (FS) of left ventricle (LV) and lung weight were significantly reduced in E6446 group compared to saline group. Furthermore, the infiltration of inflammatory cells including macrophages in the TAC-operated heart was inhibited by E6446. Next, mice with LV dysfunction at 2 weeks after TAC were subjected to the oral administration with E6446 or saline every two days for 4 weeks. The LV chamber size was significantly smaller and FS was higher in E6446 group than those in saline group 6 weeks after TAC. Our study showed that E6446 prevented the development of LV dilatation and dysfunction with inflammation and slowed progression of cardiac remodeling induced by pressure overload. E6446 might be a novel therapeutic to treat patients with heart failure.
Noradrenergic signaling in the wakeful state inhibits microglial surveillance and synaptic plasticity in the mouse visual cortex
Authors: Rianne D. Stowell, Grayson O. Sipe, Ryan P. Dawes, Hanna N. Batchelor, Katheryn A. Lordy, Brendan S. Whitelaw, Mark B. Stoessel, Jean M. Bidlack, Edward Brown, Mriganka Sur, Ania K. Majewska
Journal: Nature Neuroscience (2019)
Abstract 507: Activation of Transient Receptor Potential Canonical Channel Currents in Iron-Overloaded Cardiac Myocytes
Authors: Natthaphat Siri-Angkul, Richard Gordan, Suwakon Wongjaikam, Nadezhda Fefelova, Judith Gwathmey, Siriporn Chattipakorn, Nipon Chattipakorn, Lai-Hua Xie
Journal: Circulation Research (2019)

Background: Iron (Fe) overload cardiomyopathy is the leading cause of death in hemochromatotic patients, yet the mechanistic insight is still incomplete and controversial. We investigated alterations of action potentials (APs), ionic currents, and intracellular Ca 2+ (Ca 2+ i ) in Fe-loaded mouse cardiomyocytes, as well as functional impacts of Fe overload on single-cell contraction and whole-heart arrhythmias. Methods: Cardiomyocytes were isolated from left ventricles of mouse hearts and were superfused with Fe 3+ /8-hydroxyquinoline complex (5-100 μM). APs, L-type Ca 2+ currents (I Ca,L ), total outward K + currents (I K ), and transient receptor potential canonical (TRPC) channel currents were recorded by the patch-clamp technique. Ca 2+ i was evaluated by using Fluo-4. Cell contraction was measured by a video-based edge detection system. Arrhythmias were evaluated in Langendorff-perfused hearts under S 1 -S 2 stimulation protocol. Results: Persistent Fe (15 μM) treatment prolonged AP duration at 90% repolarization (APD 90 : 46.8 ± 2.8 vs. 203.6 ± 63.4 ms, p&lt;0.05), induced early and delayed afterdepolarizations (EADs: 0 % vs. 45.0 ± 15.0 %; DADs: 4.3 ± 1.4 vs. 27.0 ± 7.0 %, p&lt;0.05, respectively) in mouse cardiomyocytes. Consistently, arrhythmia incidence was increased in Fe 3+ /8-HQ-perfused hearts. Fe treatment decreased peak I Ca,L (16.5 ± 1.7 vs.11.4 ± 1.3 pA/pF, p&lt;0.01) and I K (59.2 ± 3.3 vs. 50.4 ± 3.0 pA/pF, p&lt;0.01), altered Ca 2+ i transient patterns and decreased contractility (4.8 ± 0.5 vs. 3.5 ± 0.4%, p&lt;0.01). During the late phase of Fe treatment, fast Ca 2+ waves and sustained depolarization were induced to generate a secondary (shallow) resting membrane potential (RMP: from -68.8 ± 0.6 to -25.0 ± 3.7 mV) where the myocytes became unexcitable. Gadolinium, a TRPC channel blocker, abolished fast Ca 2+ waves and reversed RMP to the deep level (-62.9 ± 3.5 mV). The involvement of TRPC activation was determined for the first time by recording TRPC current and assessing the effect of functional TRPC channel antibodies. Conclusions: In mouse cardiomyocytes, Fe overload induced arrhythmogenic APD prolongation and EADs/DADs, aberrant Ca 2+ i dynamics, and impaired contractility. The activation of TRPC channels accounts for an important underlying mechanism.
Activin A, a Potential Key Factor of the Malignant Bone Marrow Niche, Enhances B-Cell Precursor-Acute Lymphoblastic Leukemic Cell Migratory and Invasive Properties
Authors: Erica Dander, Federica Portale, Daniela Silvestri, Giulia Cricrì, Silvia Bresolin, Stefania Gaspari, Barbara Russo, Monica Lupi, Paolo Ubezio, Geertruy te Kronnie, Maria Grazia Valsecchi, Franco Locatelli, Carmelo Rizzari, Andrea Biondi, Giovanna D'Amico
Journal: Blood (2018)
Abstract 528: Restricted Proteasome Heterogeneity Promotes Premature Heart Failure and Deterioration of Associated Protein Levels Upon Continuous β-Adrenergic Stimulation
Authors: Felix A Trogisch, Franziska Koser, Andreas Jungmann, Oliver J Müller, Markus Hecker, Oliver Drews
Journal: Circulation Research (2019)

Introduction: The ubiquitin proteasome-system is a main contributor to cellular proteostasis. The dynamic regulation of proteasome composition and function during cardiac remodeling has been of high interest. To what extend discrete proteasome subunits in turn modify cardiac remodeling, is poorly understood. Objective: Aim of the study was to investigate the contribution of the non-essential proteasome subunit low molecular mass peptide 2 (Lmp2) on cardiac function, tissue and proteome upon induced hypertrophic remodeling. Methods &amp; Results: We found induction of cardiac Lmp2 during isoproterenol (Iso)- and TAC-induced remodeling and hypertrophic cardiomyopathy. Unchallenged adult mice congenitally lacking Lmp2 (KO) were indistinguishable from their WT littermates. After 7 days of continuous Iso administration (30 mg/kg/d) though, cardiac function was significantly reduced in Lmp2 KO mice as compared to WT (fractional shortening: -32% vs. WT, p&lt;0.01, n≥9). Interestingly, reduced cardiac function was accompanied by augmented cardiac remodeling as shown by heart weight to body weight ratio, wall thickness, cardiomyocyte cross-sectional area and interstitial collagen content. Cardiac-restricted re-expression of Lmp2 utilizing AAV9-mediated gene transfer rescued cardiac function and restricted remodeling to WT levels, attributing those findings to cardiac Lmp2. Hence, we analyzed the cardiac proteome utilizing 2-D DIGE. Out of approximately 1500 detected protein spots, 114 were showing significant differences upon cardiac remodeling depending on absolute Lmp2 protein expression (p≤0.05). All spots were manually inspected for correct matching across 10 gels. Subsequently, spots were picked with priority on those with the most prominent changes in abundance and identified by mass spectrometry. For example, we found significantly less carbonic anhydrase 2 and manganese superoxide dismutase in the remodeled myocardium of WT compared to Lmp2 KO mice. Conclusions: Cardiac lack of Lmp2 exacerbates cardiac remodeling, which is reflected in the cardiac proteome by deteriorated levels of proteins with a known pivotal role in human cardiac disease.
Lack of HLA Class I Ligands for Autologous Inhibitory KIR Is Associated with Improved Survival Following Autologous Stem Cell Transplant for Children with Neuroblastoma.
Authors: Jeffrey M Venstrom, Junting Zheng, Reenat S Hasan, Karen E Danis, Irene Y Cheung, Bo Dupont, Nai Kong Cheung, Katharine C Hsu
Journal: Blood (2008)
Nasal Pneumococcal Density Is Associated with Microaspiration and Heightened Human Alveolar Macrophage Responsiveness to Bacterial Pathogens
Authors: Elena Mitsi, Beatriz Carniel, Jesús Reiné, Jamie Rylance, Seher Zaidi, Alessandra Soares-Schanoski, Victoria Connor, Andrea M. Collins, Andreas Schlitzer, Elissavet Nikolaou, Carla Solórzano, Sherin Pojar, Helen Hill, Angela D. Hyder-Wright, Kondwani C. Jambo, Marco R. Oggioni, Megan De Ste Croix, Stephen B. Gordon, Simon P. Jochems, Daniela M. Ferreira
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Pneumococcal pneumonia remains a global health problem. Colonization of the nasopharynx with Streptococcus pneumoniae (Spn), although a prerequisite of infection, is the main source of exposure and immunological boosting in children and adults. However, our knowledge of how nasal colonization impacts on the lung cells, especially on the predominant alveolar macrophage (AM) population, is limited.Objectives: Using a controlled human infection model to achieve nasal colonization with 6B serotype, we investigated the effect of Spn colonization on lung cells.Methods: We collected BAL from healthy pneumococcal-challenged participants aged 18-49 years. Confocal microscopy and molecular and classical microbiology were used to investigate microaspiration and pneumococcal presence in the lower airways. AM opsonophagocytic capacity was assessed by functional assays in vitro, whereas flow cytometry and transcriptomic analysis were used to assess further changes on the lung cellular populations.Measurements and Main Results: AMs from Spn-colonized individuals exhibited increased opsonophagocytosis to pneumococcus (11.4% median increase) for approximately 3 months after experimental pneumococcal colonization. AMs also had increased responses against other bacterial pathogens. Pneumococcal DNA detected in the BAL samples of Spn-colonized individuals were positively correlated with nasal pneumococcal density (r = 0.71; P = 0.029). Similarly, AM-heightened opsonophagocytic capacity was correlated with nasopharyngeal pneumococcal density (r = 0.61, P = 0.025).Conclusions: Our findings demonstrate that nasal colonization with pneumococcus and microaspiration prime AMs, leading to brisker responsiveness to both pneumococcus and unrelated bacterial pathogens. The relative abundance of AMs in the alveolar spaces, alongside their potential for nonspecific protection, render them an attractive target for novel vaccines.
Fatty airways: implications for obstructive disease
Authors: John G. Elliot, Graham M. Donovan, Kimberley C.W. Wang, Francis H.Y. Green, Alan L. James, Peter B. Noble
Journal: European Respiratory Journal (2019)

Epidemiological studies report that overweight or obese asthmatic subjects have more severe disease than those of a healthy weight. We postulated that accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. Our aim was to determine the relationship between adipose tissue within the airway wall and body mass index (BMI) in individuals with and without asthma. Transverse airway sections were sampled in a stratified manner from post mortem lungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities. BMI ranged from 15 to 45 kg·m −2 and was greater in nonfatal asthma cases (p&lt;0.05). Adipose tissue was identified in the outer wall of large airways (Pbm &gt;6 mm), but was rarely seen in small airways (Pbm &lt;6 mm). Adipose tissue area correlated positively with eosinophils and neutrophils in fatal asthma (Pbm &gt;12 mm, p&lt;0.01), and with neutrophils in control subjects (Pbm &gt;6 mm, p=0.04). These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight individuals may contribute to airway pathophysiology.
Characterization of Philadelphia-Negative Myeloproliferative Neoplasms in the Chilean Public Health System: Multicentric Study
Authors: Ximena Valladares, Christine Rojas, Camila Peña, Claudia Gajardo, Maria Elena Cabrera, Rodrigo Valenzuela, Virginia Monardes, Hernán López-Vidal, Marcelo Abarca, Pilar León, Rocío Osorio, Erika Pérez, Pablo Soto, Gabriel La Rocca, Daniela Cardemil, Marvila Intriago, Vivianne Torres
Journal: Blood (2018)
Anti-Angiogenic In Vivo Effect of Lenalidomide (CC-5013) in Myelodysplastic Syndrome with del(5q) Chromosome Abnormality and Its Relation to the Course of Disease.
Authors: Guntram Buesche, Stephanie Dieck, Aristoteles Giagounidis, Oliver Bock, Ludwig Wilkens, Brigitte Schlegelberger, Robert Knight, John Bennett, Carlo Aul, Hans H. Kreipe
Journal: Blood (2005)
Mediastinal Mass, Triglycerides Level Above 1000mg/Dl and Intensive Dexamethasone and Asparaginase Treatment Are Risk Factors for Cerebral Sinus Venous Thrombosis in Children Treated for Acute Lymphoblastic Leukemia at the Children's Cancer Center of Lebanon
Authors: Habib El-Khoury, Khaled M Ghanem, Yaacoub Mubarak, Nidale Tarek, Hassan El Solh, Anthony K.C. Chan, Carole Aridi, Miguel R. Abboud, Raya Saab, Samar A. Muwakkit
Journal: Blood (2018)
Abstract 211: Substrate Elasticity Impacts Duchenne Muscular Dystrophy Cardiomyopathy Progression
Authors: Gaspard Pardon, Alex C Chang, Beth L Pruitt, Helen M Blau
Journal: Circulation Research (2019)

Duchenne Muscular Dystrophy (DMD) is a X-link disease affecting ~1:3500 boys per year and culminating with heart failure in early adulthood. DMD results from &gt;200 possible genetic mutations on dystrophin. The lack of dystrophin disrupts the anchoring of the cell sarcomere to the extracellular matrix (ECM), affecting the cardiac contraction. With disease progression, in an attempt to mitigate the subcellular defects, the tissue stiffness and ECM composition remodel in association with a dilated cardiomyopathy phenotype and fibrosis. Our hypothesis is that disease progression is accelerating because of this remodelling, through a positive feedback loop involving multiple mechanosensing pathways. Here, we use a single-cell assay platform to model the effect of fibrotic remodelling in DMD. This platform allows measuring the force production of single human-derived pluripotent stem cell (hiPSC) cardiomyocytes (CMs). The substrate stiffness can be controlled to match that of healthy (~10kPa) or fibrotic (~35kPa) tissue. In addition, single iPSC-CMs are patterned in an elongated 1:7 aspect ratio using microcontact printing of ECM protein. This enhances their intracellular structural maturity towards a more mature adult phenotype. This renders our in-vitro model more representative of the human pathology and greatly improves our measurements standardization. Our results show that single iPSC-CMs with DMD mutations have a dramatically reduced ability to produce force on stiffer substrates compared to their isogenic control. This loss of contractile function correlates with an increase in reactive oxygen species (ROS) and mitochondria dysfunction, as well as with other markers of stress response and cellular senescence.We are asking how the remodeling of the ECM stiffness and composition is signaled from the outside-in and affects the progression of the disease phenotype. The further development of our platform and approach will allow for more accurate in-vitro modeling of cardiac diseases and greatly increase our understanding of the underlying biophysics of mechanosensing.