tbuckley/cabot-search huggingface dataset:
Abstract P412: Mitochondrial Metabolic Transcriptome Profiles During Cardiomyocyte Differentiation From Mouse And Human Pluripotent Stem Cells
Authors: Sung Woo Cho, Hyoung Kyu Kim, Jin Han, Ji-Hee Sung
Journal: Circulation Research (2021)

Simultaneous increase of myofibrils and mitochondria is a key process of cardiomyocyte differentiation from pluripotent stem cells (PSCs). Specifically, development of mitochondrial oxidative energy metabolism in cardiomyocytes is essential to providing the beating function. Although previous studies reported that mitochondrial oxidative metabolism have some correlation with the differentiation of cardiomyocytes, the mechanism by which mitochondrial oxidative metabolism is regulated and the link between cardiomyogenesis and mitochondrial function are still poorly understood. In the present study, we performed transcriptome analysis on cells at specific stages of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs). We selected highly upregulated mitochondrial metabolic genes at cardiac lineage commitment and time-dependent manner during cardiomyocyte differentiation and identified the protein-protein interaction network connecting between mitochondrial metabolic and cardiac developmental genes. We found several mitochondrial metabolic regulatory genes at cardiac lineage commitment (Cck, Bdnf, Fabp4, Cebpa, Cdkn2a in mESC-derived cells and CCK, NOS3 in hiPSC-derived cells) and time-dependent manner during cardiomyocyte differentiation (Eno3, Pgam2, Cox6a2, Fabp3 in mESC-derived cells and PGAM2, SLC25A4 in hiPSC-derived cells). Notably, mitochondrial metabolic proteins are highly interacted with cardiac developmental proteins time-dependent manner during cardiomyocyte differentiation rather than cardiac lineage commitment. Furthermore, mitochondrial metabolic proteins are mainly interacted with cardiac muscle contractile proteins rather than cardiac transcription factors in cardiomyocyte. Therefore, mitochondrial metabolism is critical at cardiac maturation rather than cardiac lineage commitment.
Abstract 10638: The Time to Reach the Minimum Freezing Temperature During Cryoablation is a Predictor of First-Pass Conductional Block of Cavotricuspid Isthmus
Authors: Minoru Nodera, Kazuaki Amami, Naoko Hijioka, Shinya Yamada, Takashi Kaneshiro, Yasuchika Takeishi
Journal: Circulation (2021)

Background: Ablation using cryothermal energy has several potential advantages over radiofrequency (RF) ablation including a greater catheter stability due to adherence to the myocardial tissue during applications, reduced risk of thrombus formation, less pain, and etc. Several studies have reported the effects of cryoablation for the treatment of the cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) with similar efficacy and safety rates as reported for RF ablation. However, the details of freezing profile during CTI cryoablation still remain unknown. Methods: This study included 40 consecutive patients (32 men; 65±10 years) who underwent CTI cryoablation for common AFL. Patients were divided into 2 groups: one pass group who achieved first-pass conductional block of the CTI (n=30) and non-one pass group who did not (n=10). CTI ablation was performed with 2.5-min freezing cycle and 8-mm tip cryocatheters. A multidetector computed tomography scan with contrast injection which was performed before ablation in all the patients. We examined temperature changes at the catheter tip during first pass in CTI cryoablation and anatomical features of CTI in three regions: anterior, middle, and posterior. Results: There was no significant difference in the minimum freezing temperature between the one pass group and the non-one pass group (-82.6±1.6 vs. -83.2±1.2°C, P=0.245) in all the three regions. However, only in the anterior CTI, the time to reach the minimum freezing temperature was significantly shorter in the one pass group than in the non-one pass group (31.4±5.9 vs. 38.7±8.6 sec, P=0.012). The thickness of the anterior CTI was significantly thinner in the one pass group than in the non-one pass group (4.1±1.2 vs. 5.5±1.3 mm, P=0.021). On the other hand, there was no significant difference in the thickness of the middle and posterior CTI between the two groups. The time to reach the minimum freezing temperature showed a significant positive correlation with the thickness of the CTI (R=0.415, P&lt;0.001). Conclusions: The time to reach the minimum freezing temperature in the anterior CTI may predict a first-pass conductional block of CTI cryoablation. The thickness of the anterior CTI may relate to this mechanism.
Abstract P479: Pathogenesis And Altered Cardiac Transcriptomic Landscape In Western Diet Treated Aged Mice Overexpressing Human Angiotensin Type 1 Receptor
Authors: Harshada Ketkar, Samantha Tang, Sudhir Jain
Journal: Circulation Research (2021)

Overexpression of human angiotensin II type 1 receptor (hAT1R) may lead to pathophysiological outcomes due to overactivation of the renin angiotensin system. We have shown that transgenic (TG) mice containing Hap-I (hypertensive genotype) of human AT1R gene are more prone to develop metabolic syndrome (MetS) as compared to TG mice with Hap-II (normotensive genotype). The increased risk of MetS, especially in hypertension, compounded by the effects of aging and Western diet (WD), which may lead to cardiac complications. However, the underlying mechanisms are not well examined. For this purpose, we studied the pathophysiological changes and gene expression profile alterations in the heart of aged Hap-I and Hap-II TG mice following exposure to WD. Aged mice (20-24 months of age) were maintained on a regular diet or high fat diet with 2% NaCl (WD) for 16 weeks. On regular diet, aged Hap-I mice presented higher (~9 mmHg) systolic blood pressure with respect to age-matched Hap-II animals. Following administration of WD, blood pressure increased in both groups of mice, but to a larger extent in Hap-I animals (~15 mmHg), in comparison to Hap-II (~7 mmHg). With respect to Hap-II, aged Hap-I mice on regular diet tended to have larger heart weight-to-body weight ratio and higher levels of fibrosis. Western Diet treatment exacerbated these differences. RNA sequencing data from cardiac tissue of WD treated Hap-I aged mice (compared to control diet treated age-matched mice) revealed that WD significantly altered the expression of &gt;500 genes (p-adj. &lt;0.05). Bioinformatics analysis, using Qiagen IPA software, identified major alterations in main canonical pathways involved in cardiac function, inflammation, and oxidative damage. Top hits in the disease and biological function category included arrhythmia, chamber enlargement, and cell death. Importantly, IRF3, IRF7, IFNG and STAT1 were among the top upstream regulators significantly affected by WD. Overall, these results indicate that Western diet promotes hypertension, hypertrophy, and fibrosis in the heart of aged mice. Results from these studies will assist in the identification of novel molecules and mechanisms involved in hypertension and associated cardiac pathophysiology.
Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience from the Spanish Group of Hematopoietic Transplant (GETH-TC)
Authors: Rebeca Bailen, Jose Luis Vicario, Beatriz Herruzo, Luisa Maria Guerra, Ana Vallés, Albert Esquirol, Marta Fonseca, Laura Solán, Irene Sanchez Vadillo, Leyre Bento, Ariadna Pérez Martínez, Anna Torrent, Joud Zanabili, Maria Calbacho, Raquel Alenda, Miguel Ángel Moreno, Beatriz Gago, Anabelle Chinea, Irene García-Cadenas, Francisco Boix-Giner, José Luis López Lorenzo, Karem Humala, Cynthia Acosta-Fleitas, Antonia Sampol, Gillen Oarbeascoa, Javier Anguita, Jose L. Diez-Martin, Mi Kwon
Journal: Blood (2021)
CPX-351 for Acute Myeloid Leukaemia: Real World Results Are Comparable to Trial Outcomes and Exceeds Them in Non-Adverse Risk Patients- a Multicentre Experience from West Midlands Hospitals on Behalf of West Midlands Research Consortium ( WMRC) UK
Authors: Vidhya Murthy, Richard Whitmill, Clare Lodwick, Peter Dyer, Maria Ahmed, Rehmatullah Khan, Shankara Paneesha, Nicholas Pemberton, Manoj Raghavan
Journal: Blood (2021)
Abstract 12974: Transthyretin Amyloid Cardiomyopathy Associated With the P.V142I Transthyretin Variant is an Inherently Aggressive Form of Transthyretin Amyloid Cardiomyopathy Associated With Significant Functional Impairment and Poor Prognosis
Authors: Yousuf Razvi, Sashiananthan Ganesananthan, Liza Chacko, Rishi Patel, Iona Blakeney, Nandita Kaza, Steven Law, Dorota Rowczenio, Janet Gilbertson, David Hutt, Shameem Mahmood, Helen Lachmann, Ashutosh Wechalekar, Brendan Wisniowski, Carol Whelan, Lucia Venneri, Ana Martinez-Naharro, Phillip Hawkins, Marianna Fontana, Julian D Gillmore
Journal: Circulation (2021)

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM; this equates to 1.6 million carriers in the USA. We report deep phenotyping in p.V142I ATTR-CM. Hypothesis: The phenotype of p.V142I ATTR-CM is an aggressive form of ATTR CM. Methods: A retrospective study of 395 patients with p.V142I ATTR-CM from the UK National Amyloidosis Centre. Patients were diagnosed at the Centre through a comprehensive evaluation comprising clinical and functional assessment, echocardiography, radionuclide scintigraphy, histology and biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild-type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of diagnosis) were used as a comparator group. Results: At time of diagnosis, patients with p.V142I ATTR-CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38.2%) and impairment of echocardiographic parameters; mean LVEF 43%, global longitudinal strain -9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid (51%) regurgitation. Uni and multivariate cox regression analysis identified troponin T, TR, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters and 5yr survival (27% v 46%, p&lt;0.001) were significantly worse than in wtATTR-CM. Conclusion: p.V142I ATTR-CM has an aggressive phenotype characterised by functional impairment, regurgitant valvular disease and systolic impairment resulting in poor survival. LV systolic impairment, TAPSE, serum troponin and TR were independent predictors of survival, whereas LV wall thickness was not, suggesting as yet unrecognised disease mechanisms.
CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice
Authors: Biju Bhargavan, Shawna M. Woollard, Jo Ellyn McMillan, Georgette D. Kanmogne
Journal: Molecular Neurodegeneration (2021)

Abstract Background Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer’s Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies. Methods NOD/scid–IL-2Rγ c null mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal’s blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA. Results HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor–related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist. Conclusions Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies.
Abstract 14153: Novel Tools to Decipher the Molecular Regulation of the Mitochondrial Sodium-Calcium Exchanger, NCLX
Authors: Joanne F Garbincius, Oniel Salik, Adam S Mangold, Angelina D Makhoul, Emma Murray, Michael P Lazaropolous, Dhanendra Tomar, Pooja Jadiya, John W Elrod
Journal: Circulation (2021)

The precise control of mitochondrial calcium ( m Ca 2+ ) exchange allows the cardiomyocyte to balance the regulation of mitochondrial metabolism against the risk of m Ca 2+ overload and cell death. The mitochondrial sodium-calcium exchanger (NCLX) is a major route of m Ca 2+ efflux and thus is one of the key proteins that govern m Ca 2+ homeostasis. Recent studies have demonstrated that increasing NCLX-dependent m Ca 2+ efflux is a promising therapeutic objective for pathologies characterized by deleterious m Ca 2+ overload such as ischemia-reperfusion injury, heart failure, and neurodegeneration. A substantial barrier to the development of NCLX-based therapies is that no pharmacologic activators of NCLX are currently available, and indeed, very little is known about the fundamental mechanisms that stimulate or inhibit NCLX activity in vivo . Therefore, we generated a plasmid encoding a biotin ligase domain fused to the C-terminus of human NCLX (hNCLX-BioID2HA) and used this construct to perform an in vitro proximity biotinylation screen for the unbiased detection of proteins that interact with NCLX and/or modulate NCLX function. We identified ~120 candidate NCLX-proximal mitochondrial proteins in AC16 cardiomyocytes and ~80 in HeLa cells, including several of unknown function. Twenty-five proteins were detected in both data sets, suggestive of conserved function between these two cell types. Current studies are defining the specific molecular function of these mitochondrial proteins and their effects on NCLX expression, NCLX activity, and overall m Ca 2+ homeostasis. We are also developing a novel NCLX-3xFLAG knock-in mouse model to enable in vivo expression of C-terminal epitope-tagged NCLX under the control of the endogenous murine promoter. We expect this model to aid in overcoming the significant proteomic challenges of manipulating this 13-transmembrane protein. Together, these approaches will help to uncover the post-translational mechanisms that regulate NCLX-dependent m Ca 2+ efflux and to identify new therapeutic targets for heart failure and other diseases characterized by disrupted m Ca 2+ homeostasis.
Parental Leave—Are We Implementing Perspectives Rather Than Policies?
Authors: Kyla P. Terhune, Cary B. Aarons
Journal: JAMA Surgery (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
TAMI-33. DYNAMICS OF MICROGLIAL ACTIVATION AND EXPRESSION OF CYTOKINES IN THE SITE OF GLIOBLASTOMA TUMOR RESECTION
Authors: Jescelica Ortiz-Rivera, Lilia Kucheryavykh, Alejandro Albors
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma (GBM) is the most aggressive type of brain cancer. GBM tumors are made up of a large percentage of microgliawhich support the invasive nature of tumor and the resistance to therapy. In the tumor, microglia cells can polarize into M1 and M2 phenotypes. M1 phenotype is distinguished by its ability to eliminate tumor cells, and secrete proinflammatory cytokines, whileM2 phenotype is associated with tumor cell survival and secrete anti-inflammatory cytokines. Tumor resection is one of the primary steps to treat GBM, thus, resulting in tissue damage and causing microglia activation in the surgical area. The activation state of microglia in the site of resection and the impact of microglia on glioma regrowth is unclear. The purpose of this study is to investigate the state of microglia in the tumor resection area and kinetics of microglial activation.C57BL/6/GL261 mouse glioma implantation model was used. 14 days after in-brain implantation of GL261 cells tumors were surgically resected and then re-grown tumors were analyzed at 0 hours,1, 4, 7, 14 and 21 days after tumor resection, together with the originally resected primary tumors. Microglia were purified from tumors with use of magnetic beads. Western blot analysis of microglia, purified from primary and re-grown tumors, demonstrated increase of CD86 (M1) during the first 7 days after resection and then up-regulation of Arginase (M2) in a period from 14thto 21st days after tumor resection. The cytokine expression analysis revealed significant up-regulation of Vascular Endothelial Growth Factor (VEGF) and Monocyte Chemoattractant Protein 1 (MCP1) in microglia purified from re-grown tumors. PCR analysis confirmed these data, indicating increase of VEGF, MCP1 gene expression in tumor infiltrating microglia in re-grown tumor. We can state that microglia infiltrating primary tumor and tumor re-grown after surgical resection, represent significantly different cytokines expression patterns, favorable to increased vascularization and tumor progression.
Abstract 11496: Increased Pulmonary Microvascular Endothelial Permeability by E-Cigarette Aerosol: The Pathway from Lung to Peripheral Blood Vessels
Authors: Leila Mohammadi, Daniel D Han, Xiaohui Fang, Fengyun Xu, Ronak Derakhshandeh, Judith Hellman, Jeffrey Gotts, Matthew L Springer
Journal: Circulation (2021)

Background: We reported that permeability of cultured microvascular endothelial cells is increased by incubation in e-cigarette (e-cig) users’ serum relative to that from smokers or non-users. It is unclear whether this is a direct effect of aerosol chemicals that reach the circulation, or an indirect response mediated by the e-cig users’ pulmonary epithelium. Hypothesis: Vaping increases microvascular endothelial permeability indirectly by signaling from alveolar epithelium. Methods: E-cig aerosol condensates were derived from e-liquids with and without nicotine (12 mg/mL free base), each containing menthol, vanillin, ethyl maltol, or cinnamaldehyde (2 mg/mL). Cell permeability was measured in human lung microvascular endothelial cells (HMVEC-Ls) using electric cell-substrate impedance sensing. Human Type II lung alveolar epithelial cells (ATII) were grown in serum-free air-liquid interface and exposed to e-cig aerosols with 0, 18, or 36 mg/mL nicotine (free base and salt), or air, 1 h/day for 3 days in an exposure chamber inside a CO 2 incubator. Results: Incubation of HMVEC-Ls with 0.3% v/v e-cig aerosol condensates from most e-liquids, with and without nicotine, decreased cell permeability (in contrast to the increased permeability that we reported from incubation with e-cig user serum). The exception was menthol + nicotine, which increased permeability (but reduced viability). When HMVEC-Ls were instead incubated with supernatant collected from ATII cells after exposure to e-cig aerosols, permeability was increased when supernatants were from exposure to aerosol with 36 mg/ml nicotine salt, but not 36 or 18 mg/mL freebase nicotine. Supernatants from similarly exposed ATII cells contained higher levels of the proinflammatory proteins MCP-1, IL-8, GROα, and MIP-1β when aerosol contained 36 mg/mL freebase nicotine (3/6 wells) or nicotine salt (5/6), but not 18 mg/ml nicotine (0/6). Conclusion: HVMEC-L permeability was not directly increased by e-cig aerosol condensate, but was increased by supernatant of alveolar epithelial cells exposed to high-nicotine aerosol, potentially mediated by elevated ATII cytokine production, indicating a potential indirect mechanism by which vaping increases pulmonary microvascular permeability.