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A potential therapeutic role for angiotensin-converting enzyme 2 in human pulmonary arterial hypertension.
Hemnes AR, Rathinasabapathy A, Austin EA, Brittain EL, Carrier EJ, Chen X, Fessel JP, Fike CD, Fong P, Fortune N, Gerszten RE, Johnson JA, Kaplowitz M, Newman JH, Piana R, Pugh ME, Rice TW, Robbins IM, Wheeler L, Yu C, Loyd JE, West J
(2018) Eur Respir J 51:
MeSH Terms: Adult, Aged, Animals, Biomarkers, Cytokines, Female, Gene Expression, Humans, Hypertension, Pulmonary, Male, Middle Aged, Peptidyl-Dipeptidase A, Pilot Projects, Proof of Concept Study, Proto-Oncogene Proteins, Pulmonary Artery, Receptors, G-Protein-Coupled, Superoxide Dismutase, Swine, Vascular Resistance
Show Abstract · Added March 26, 2019
Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
Copyright ©ERS 2018.
0 Communities
2 Members
0 Resources
20 MeSH Terms
Gene expression in triple-negative breast cancer in relation to survival.
Wang S, Beeghly-Fadiel A, Cai Q, Cai H, Guo X, Shi L, Wu J, Ye F, Qiu Q, Zheng Y, Zheng W, Bao PP, Shu XO
(2018) Breast Cancer Res Treat 171: 199-207
MeSH Terms: Adult, Aged, Biomarkers, Tumor, Female, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Neoplasm Grading, Neoplasm Staging, Population Surveillance, Prognosis, Registries, Survival Analysis, Triple Negative Breast Neoplasms
Show Abstract · Added December 6, 2018
PURPOSE - The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression.
METHODS - We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources.
RESULTS - Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS.
CONCLUSIONS - We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.
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1 Members
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16 MeSH Terms
Na -K -2Cl Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia.
Delpire E, Gagnon KB
(2018) Compr Physiol 8: 871-901
MeSH Terms: Animals, Biological Transport, Cell Membrane, Epithelial Cells, Gene Expression Regulation, Humans, Sodium-Potassium-Chloride Symporters, Structure-Activity Relationship
Show Abstract · Added April 2, 2019
Two genes encode the Na -K -2Cl cotransporters, NKCC1 and NKCC2, that mediate the tightly coupled movement of 1Na , 1K , and 2Cl across the plasma membrane of cells. Na -K -2Cl cotransport is driven by the chemical gradient of the three ionic species across the membrane, two of them maintained by the action of the Na /K pump. In many cells, NKCC1 accumulates Cl above its electrochemical potential equilibrium, thereby facilitating Cl channel-mediated membrane depolarization. In smooth muscle cells, this depolarization facilitates the opening of voltage-sensitive Ca channels, leading to Ca influx, and cell contraction. In immature neurons, the depolarization due to a GABA-mediated Cl conductance produces an excitatory rather than inhibitory response. In many cell types that have lost water, NKCC is activated to help the cells recover their volume. This is specially the case if the cells have also lost Cl . In combination with the Na /K pump, the NKCC's move ions across various specialized epithelia. NKCC1 is involved in Cl -driven fluid secretion in many exocrine glands, such as sweat, lacrimal, salivary, stomach, pancreas, and intestine. NKCC1 is also involved in K -driven fluid secretion in inner ear, and possibly in Na -driven fluid secretion in choroid plexus. In the thick ascending limb of Henle, NKCC2 activity in combination with the Na /K pump participates in reabsorbing 30% of the glomerular-filtered Na . Overall, many critical physiological functions are maintained by the activity of the two Na -K -2Cl cotransporters. In this overview article, we focus on the functional roles of the cotransporters in nonpolarized cells and in epithelia. © 2018 American Physiological Society. Compr Physiol 8:871-901, 2018.
Copyright © 2018 American Physiological Society. All rights reserved.
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1 Members
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8 MeSH Terms
Single-Cell Transcriptomic Profiling of Pluripotent Stem Cell-Derived SCGB3A2+ Airway Epithelium.
McCauley KB, Alysandratos KD, Jacob A, Hawkins F, Caballero IS, Vedaie M, Yang W, Slovik KJ, Morley M, Carraro G, Kook S, Guttentag SH, Stripp BR, Morrisey EE, Kotton DN
(2018) Stem Cell Reports 10: 1579-1595
MeSH Terms: Animals, Cell Differentiation, Cell Line, Cell Lineage, Cell Plasticity, Epithelium, Gene Expression Profiling, Genes, Reporter, Humans, Induced Pluripotent Stem Cells, Kinetics, Lung, Mice, Secretoglobins, Sequence Analysis, RNA, Single-Cell Analysis, Solubility, Spheroids, Cellular, Time Factors, Transcriptome, Wnt Signaling Pathway
Show Abstract · Added April 1, 2019
Lung epithelial lineages have been difficult to maintain in pure form in vitro, and lineage-specific reporters have proven invaluable for monitoring their emergence from cultured pluripotent stem cells (PSCs). However, reporter constructs for tracking proximal airway lineages generated from PSCs have not been previously available, limiting the characterization of these cells. Here, we engineer mouse and human PSC lines carrying airway secretory lineage reporters that facilitate the tracking, purification, and profiling of this lung subtype. Through bulk and single-cell-based global transcriptomic profiling, we find PSC-derived airway secretory cells are susceptible to phenotypic plasticity exemplified by the tendency to co-express both a proximal airway secretory program as well as an alveolar type 2 cell program, which can be minimized by inhibiting endogenous Wnt signaling. Our results provide global profiles of engineered lung cell fates, a guide for improving their directed differentiation, and a human model of the developing airway.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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1 Members
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21 MeSH Terms
Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca Sensitivity of Insulin Secretion Vesicles.
Huang C, Walker EM, Dadi PK, Hu R, Xu Y, Zhang W, Sanavia T, Mun J, Liu J, Nair GG, Tan HYA, Wang S, Magnuson MA, Stoeckert CJ, Hebrok M, Gannon M, Han W, Stein R, Jacobson DA, Gu G
(2018) Dev Cell 45: 347-361.e5
MeSH Terms: Animals, Biological Transport, Calcium, Cell Differentiation, Female, Gene Expression Regulation, Glucose, Humans, Hypoglycemic Agents, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Sweetening Agents, Synaptotagmins
Show Abstract · Added April 17, 2018
Islet β cells from newborn mammals exhibit high basal insulin secretion and poor glucose-stimulated insulin secretion (GSIS). Here we show that β cells of newborns secrete more insulin than adults in response to similar intracellular Ca concentrations, suggesting differences in the Ca sensitivity of insulin secretion. Synaptotagmin 4 (Syt4), a non-Ca binding paralog of the β cell Ca sensor Syt7, increased by ∼8-fold during β cell maturation. Syt4 ablation increased basal insulin secretion and compromised GSIS. Precocious Syt4 expression repressed basal insulin secretion but also impaired islet morphogenesis and GSIS. Syt4 was localized on insulin granules and Syt4 levels inversely related to the number of readily releasable vesicles. Thus, transcriptional regulation of Syt4 affects insulin secretion; Syt4 expression is regulated in part by Myt transcription factors, which repress Syt4 transcription. Finally, human SYT4 regulated GSIS in EndoC-βH1 cells, a human β cell line. These findings reveal the role that altered Ca sensing plays in regulating β cell maturation.
Copyright © 2018 Elsevier Inc. All rights reserved.
3 Communities
3 Members
0 Resources
17 MeSH Terms
Transposon-modified antigen-specific T lymphocytes for sustained therapeutic protein delivery in vivo.
O'Neil RT, Saha S, Veach RA, Welch RC, Woodard LE, Rooney CM, Wilson MH
(2018) Nat Commun 9: 1325
MeSH Terms: Adoptive Transfer, Animals, Cell Engineering, Cell- and Tissue-Based Therapy, DNA Transposable Elements, Erythropoietin, Gene Expression, Genetic Vectors, Hematopoiesis, Herpesvirus 4, Human, Humans, Mice, Ovalbumin, Receptors, Antigen, T-Cell, T-Lymphocytes, Transgenes, Vaccination
Show Abstract · Added September 24, 2018
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Here we report the utility of antigen-specific T lymphocytes as a regulatable peptide delivery platform for in vivo therapy. piggyBac transposon modification of murine cells with luciferase allows us to visualize T cells after adoptive transfer. Vaccination stimulates long-term T-cell engraftment, persistence, and transgene expression enabling detection of modified cells up to 300 days after adoptive transfer. We demonstrate adoptive transfer of antigen-specific T cells expressing erythropoietin (EPO) elevating the hematocrit in mice for more than 20 weeks. We extend our observations to human T cells demonstrating inducible EPO production from Epstein-Barr virus (EBV) antigen-specific T lymphocytes. Our results reveal antigen-specific T lymphocytes to be an effective delivery platform for therapeutic molecules such as EPO in vivo, with important implications for other diseases that require peptide therapy.
0 Communities
2 Members
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17 MeSH Terms
Macrophage-Targeted Therapeutics for Metabolic Disease.
Peterson KR, Cottam MA, Kennedy AJ, Hasty AH
(2018) Trends Pharmacol Sci 39: 536-546
MeSH Terms: Drug Delivery Systems, Gene Expression, Humans, Macrophages, Metabolic Diseases, Molecular Targeted Therapy, Pharmaceutical Preparations
Show Abstract · Added March 26, 2019
Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.
Published by Elsevier Ltd.
0 Communities
1 Members
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MeSH Terms
A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel.
Johnson CN, Potet F, Thompson MK, Kroncke BM, Glazer AM, Voehler MW, Knollmann BC, George AL, Chazin WJ
(2018) Structure 26: 683-694.e3
MeSH Terms: Binding Sites, Calcium, Calmodulin, Crystallography, X-Ray, Gene Expression Regulation, Humans, Kinetics, Models, Molecular, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Protein Binding
Show Abstract · Added March 26, 2019
The function of the human cardiac sodium channel (Na1.5) is modulated by the Ca sensor calmodulin (CaM), but the underlying mechanism(s) are controversial and poorly defined. CaM has been reported to bind in a Ca-dependent manner to two sites in the intracellular loop that is critical for inactivation of Na1.5 (inactivation gate [IG]). The affinity of CaM for the complete IG was significantly stronger than that of fragments that lacked both complete binding sites. Structural analysis by nuclear magnetic resonance, crystallographic, and scattering approaches revealed that CaM simultaneously engages both IG sites using an extended configuration. Patch-clamp recordings for wild-type and mutant channels with an impaired CaM-IG interaction revealed CaM binding to the IG promotes recovery from inactivation while impeding the kinetics of inactivation. Models of full-length Na1.5 suggest that CaM binding to the IG directly modulates channel function by destabilizing the inactivated state, which would promote resetting of the IG after channels close.
Copyright © 2018 Elsevier Ltd. All rights reserved.
0 Communities
2 Members
0 Resources
MeSH Terms
B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.
Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV, Boothby MR
(2018) J Immunol 200: 2627-2639
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Gene Expression, Germinal Center, Immunity, Humoral, Immunoglobulin G, Immunologic Memory, Lymphocyte Activation, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred C57BL, Mutation, Plasma Cells, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Transcription Factors
Show Abstract · Added March 14, 2018
B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.
Copyright © 2018 by The American Association of Immunologists, Inc.
1 Communities
2 Members
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17 MeSH Terms
α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.
Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, Bottino R, Campbell-Thompson M, Aramandla R, Poffenberger G, Lindner J, Pan FC, von Herrath MG, Greiner DL, Shultz LD, Sanyoura M, Philipson LH, Atkinson M, Harlan DM, Levy SE, Prasad N, Stein R, Powers AC
(2018) Cell Rep 22: 2667-2676
MeSH Terms: Adolescent, Adult, Animals, Case-Control Studies, Cellular Reprogramming, Child, Diabetes Mellitus, Type 1, Female, Gene Expression Regulation, Glucagon, Glucagon-Secreting Cells, Humans, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Middle Aged, Phenotype, Tissue Donors, Transcription Factors, Young Adult
Show Abstract · Added March 8, 2018
Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
3 Members
0 Resources
21 MeSH Terms