1,055 results match your criteria Alpha1-Antitrypsin Deficiency


Alpha1-Antitrypsin Deficiency: A Cause of Chronic Liver Disease.

Clin Liver Dis 2020 Aug 2;24(3):483-492. Epub 2020 Jun 2.

3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA. Electronic address:

Alpha1-antitrypsin deficiency (A1ATD) is an inherited cause of chronic liver disease. It is inherited in an autosomal codominant pattern with each inherited allele expressed in the formation of the final protein, which is primarily produced in hepatocytes. The disease usually occurs in pediatric and elderly populations. Read More

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http://dx.doi.org/10.1016/j.cld.2020.04.010DOI Listing

α-antitrypsin PI*SZ genotype: a SERPINA1 deficiency haplotype with uncertain clinical and therapeutic implications.

Eur Respir J 2020 Jun 18;55(6). Epub 2020 Jun 18.

Materials and Energy Dept, School of Mining Engineering, Oviedo University, Oviedo, Spain.

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http://dx.doi.org/10.1183/13993003.00713-2020DOI Listing

Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis.

Sci Transl Med 2020 May;12(545)

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229-3026, USA.

Eosinophilic esophagitis (EoE) is a chronic, food antigen-driven, inflammatory disease of the esophagus and is associated with impaired barrier function. Evidence is emerging that loss of esophageal expression of the serine peptidase inhibitor, kazal type 7 (SPINK7), is an upstream event in EoE pathogenesis. Here, we provide evidence that loss of mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Read More

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http://dx.doi.org/10.1126/scitranslmed.aaz7773DOI Listing

Identification of small molecules by screening a mixture-based scaffold compound library for treatment of alpha-1 antitrypsin deficiency.

Biochem Biophys Res Commun 2020 Jun 11;527(1):317-323. Epub 2020 May 11.

Torrey Pines Institute for Molecular Studies, Port St. Lucie, Florida, USA.

This study aimed to identify small molecules that have the potential to treat alpha1-antitrypsin deficiency (AATD) by screening compounds available from a mixture-based scaffold library. 93 scaffold libraries (total diversity of >30 million compounds in mixture format) were screened using a cell model of AATD in order to identify samples that could either reduce intracellular aggregation of Z-form AAT protein, increase extracellular secretion of Z-AAT or both. Mixture libraries containing compounds with in vitro activity, for example library 1295, were screened further to identify individual active compounds. Read More

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http://dx.doi.org/10.1016/j.bbrc.2020.04.037DOI Listing

Blockade of Dopamine D2 Receptors as a Novel Approach to Stimulation of Notch1 Endothelial Progenitor Cells and Angiogenesis in C57BL/6 Mice with Pulmonary Emphysema Induced by Proteases and Deficiency of α1-Antitrypsin.

Bull Exp Biol Med 2020 Apr 23;168(6):718-723. Epub 2020 Apr 23.

Laboratory of Regenerative Pharmacology, E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Moscow, Russia.

We studied the effects of spiperone, a selective blocker of dopamine D2 receptors, on the model of pulmonary emphysema provoked by administration of elastase and D-galactosamine hydrochloride to female C57BL/6 mice and characterized by activation of proteases in the lungs and systemic deficiency of its inhibitor α1-antitrypsin. In this model, spiperone prevented the development of inflammatory reaction and reduced the area of emphysematous expanded alveolar tissue. The expression of angiogenic marker CD31 in the lungs increased under these conditions. Read More

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http://dx.doi.org/10.1007/s10517-020-04787-9DOI Listing

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis.

Int J Mol Sci 2020 Apr 19;21(8). Epub 2020 Apr 19.

Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.

Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. Read More

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http://dx.doi.org/10.3390/ijms21082855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215584PMC
April 2020
2.862 Impact Factor

Electrophoretic α1-globulin for screening of α1-antitrypsin deficient variants.

Clin Chem Lab Med 2020 Apr 22. Epub 2020 Apr 22.

Unit of Respiratory Pathophysiology and Thoracic Endoscopy - Geriatrics, Department of Medicine, Campus Bio-Medico University and Teaching Hospital, Rome, Italy.

Background Available screening procedures for the detection of α1-antitrypsin-deficient (AATD) mutations have suboptimal cost-effectiveness ratios. The aim in this study was to evaluate and compare the viability of a composite approach, primarily based on the α1-globulin fraction, in identifying AAT genetic analysis eligible patients against standard screening procedures, based on clinically compatible profiling and circulating AAT < 1 g/L. Methods A total of 21,094 subjects were screened for AATD and deemed eligible when meeting one of these criteria: α1-globulin ≤2. Read More

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http://dx.doi.org/10.1515/cclm-2020-0071DOI Listing

Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis.

Thorax 2020 Jul 17;75(7):592-593. Epub 2020 Apr 17.

Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK

Alpha-1 antitrypsin deficiency (AATD) is a cause of bronchiectasis. Guidelines for bronchiectasis from the British Thoracic Society do not recommend to routinely test patients for AATD. In contrast, guidelines for AATD recommend routine screening. Read More

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http://dx.doi.org/10.1136/thoraxjnl-2019-214195DOI Listing

Mesenchymal Stromal Cell Secretome for Severe COVID-19 Infections: Premises for the Therapeutic Use.

Cells 2020 04 9;9(4). Epub 2020 Apr 9.

.Center for Diagnosis of Inherited Alpha1-antitrypsin Deficiency, Department of Internal Medicine and Therapeutics, Pneumology Unit IRCCS San Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy.

From the end of 2019, the world population has been faced the spread of the novel coronavirus SARS-CoV-2 responsible for COVID-19 infection. In approximately 14% of the patients affected by the novel coronavirus, the infection progresses with the development of pneumonia that requires mechanical ventilation. At the moment, there is no specific antiviral treatment recommended for the COVID-19 pandemic and the therapeutic strategies to deal with the infection are only supportive. Read More

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http://dx.doi.org/10.3390/cells9040924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226831PMC

Alpha-Antitrypsin Deficiency.

N Engl J Med 2020 04;382(15):1443-1455

From the Department of Internal Medicine III, University Hospital RWTH (Rheinisch-Westfälisch Technische Hochschule) Aachen, Aachen, Germany (P.S.); the Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin (N.G.M.); and UCL Respiratory, Division of Medicine, Rayne Institute, University College London, London (D.A.L.).

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http://dx.doi.org/10.1056/NEJMra1910234DOI Listing

Molecular diagnosis of alpha1-antitrypsin deficiency: A new method based on Luminex technology.

J Clin Lab Anal 2020 Mar 17:e23279. Epub 2020 Mar 17.

Center for Diagnosis of Inherited Alpha1-antitrypsin Deficiency, Laboratory of Biochemistry and Genetics, Institute for Respiratory Disease, Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Background: Alpha1-antitrypsin deficiency (AATD) is an under-diagnosed hereditary disorder characterized by reduced serum levels of alpha1-antitrypsin (AAT) and increased risk to develop lung and liver diseases at an early age. AAT is encoded by the highly polymorphic SERPINA1 gene. The most common deficiency alleles are S and Z, but more than 150 rare variants lead to low levels of the protein. Read More

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http://dx.doi.org/10.1002/jcla.23279DOI Listing

Clinical considerations in individuals with α-antitrypsin PI*SZ genotype.

Eur Respir J 2020 Jun 18;55(6). Epub 2020 Jun 18.

Lung Investigation Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

α-Antitrypsin deficiency (AATD), characterised by reduced levels or functionality of α-antitrypsin (AAT), is a significantly underdiagnosed genetic condition that predisposes individuals to lung and liver disease. Most of the available data on AATD are based on the most common, severe deficiency genotype (PI*ZZ); therefore, treatment and monitoring requirements for individuals with the PI*SZ genotype, which is associated with a less severe AATD, are not as clear. Recent genetic data suggest the PI*SZ genotype may be significantly more prevalent than currently thought, due in part to less frequent identification in the clinic and less frequent reporting in registries. Read More

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http://dx.doi.org/10.1183/13993003.02410-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301289PMC

Protocol for the EARCO Registry: a pan-European observational study in patients with α-antitrypsin deficiency.

ERJ Open Res 2020 Jan 2;6(1). Epub 2020 Mar 2.

Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

Rationale And Objectives: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD. Read More

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http://dx.doi.org/10.1183/23120541.00181-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049712PMC
January 2020

Null: A novel α-antitrypsin allele with in cis variants Glu366Lys and Ile100Asn.

Clin Biochem 2020 May 19;79:23-27. Epub 2020 Feb 19.

Department of Pathology and Laboratory Medicine, St. Paul's Hospital, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, BC, Canada. Electronic address:

Background: α-Antitrypsin (A1AT) deficiency predisposes patients to pulmonary disease due to inadequate protection against human neutrophil elastase released during inflammatory responses. A1AT deficiency is caused by homozygosity or compound heterozygosity for A1AT variants; individuals with A1AT deficiency most commonly have at least one Z variant allele (c.1096G > A (Glu366Lys)). Read More

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http://dx.doi.org/10.1016/j.clinbiochem.2020.02.013DOI Listing

Clinical manifestations in patients with PI*MM genotypes. A matter still unsolved in alpha-1 antitrypsin deficiency.

Respirol Case Rep 2020 Apr 19;8(3):e00528. Epub 2020 Feb 19.

Department of Medicine and Surgery, Respiratory Disease and Lung Function Unit University of Parma Italy.

We report the genetic variants associated with alpha-1 antitrypsin deficiency (AATD) in 117 patients admitted to our outpatient clinic and characterized by a serum concentration of AAT lower than 113 mg/dL. We focused on the M-like heterozygous variant of the gene called PI*MM, and describe three patients with this variant. While the role of homozygous AATD in liver and pulmonary disease is well established, the association between heterozygous AATD and chronic liver and pulmonary disease is still under investigation. Read More

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http://dx.doi.org/10.1002/rcr2.528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029433PMC

α Antitrypsin therapy modulates the neutrophil membrane proteome and secretome.

Eur Respir J 2020 Apr 30;55(4). Epub 2020 Apr 30.

Irish Centre for Genetic Lung Disease, Dept of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.

Obstructive pulmonary disease in patients with α antitrypsin (AAT) deficiency (AATD) occurs earlier in life compared with patients without AATD. To understand this further, the aim of this study was to investigate whether AATD presents with altered neutrophil characteristics, due to the specific lack of plasma AAT, compared with non-AATD COPD.This study focussed on the neutrophil plasma membrane and, by use of label-free tandem mass spectrometry, the proteome of the neutrophil membrane was compared in forced expiratory volume in 1 s (FEV)-matched AATD, non-AATD COPD and in AATD patients receiving weekly AAT augmentation therapy (n=6 patients per cohort). Read More

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http://dx.doi.org/10.1183/13993003.01678-2019DOI Listing

α-Antitrypsin deficiency and chronic respiratory disorders.

Eur Respir Rev 2020 Mar 12;29(155). Epub 2020 Feb 12.

Unit of Pharmacology, Dept Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

α-antitrypsin deficiency (AATD) is a hereditary disorder associated with a risk of developing liver disease and pulmonary emphysema, and other chronic respiratory disorders (mainly asthma and bronchiectasis); Z variant is the commonest deficient variant of AAT. Determining AAT concentration in serum or plasma and identifying allelic variants by phenotyping or genotyping are fundamental in the diagnosis of AATD. Initial evaluation and annual follow-up measurement of lung function, including post-bronchodilator forced expiratory volume in 1 s and gas transfer inform on disease progression. Read More

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http://dx.doi.org/10.1183/16000617.0073-2019DOI Listing

Diagnosis and treatment of lung disease associated with alpha one-antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand.

Respirology 2020 Mar 6;25(3):321-335. Epub 2020 Feb 6.

Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash University, Melbourne, VIC, Australia.

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD-associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i. Read More

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http://dx.doi.org/10.1111/resp.13774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078913PMC

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency.

Thorax 2020 Apr 20;75(4):321-330. Epub 2020 Jan 20.

Irish Centre for Genetic Lung Disease, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.

Introduction: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy.

Methods: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. Read More

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http://dx.doi.org/10.1136/thoraxjnl-2019-214076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231451PMC

The clinical value of interleukins-8, -10, and -17 in idiopathic granulomatous mastitis.

Clin Rheumatol 2020 May 9;39(5):1671-1677. Epub 2020 Jan 9.

Department of General Surgery, London North West Healthcare NHS Trust, Northwick Park Hospital, Middlesex, London, UK.

Introduction: Idiopathic granulomatous mastitis (IGM) is a rare, chronic inflammatory benign breast disease. Although the etiology of this disease is unknown, it has been suggested that hormonal disorders, autoimmunity, smoking, and α1-antitrypsin deficiency may play a role in the etiopathogenesis. The aim is to investigate the changes in cytokine profiles including interleukin (IL)-4, -8, -10, -17, and tumor necrosis factor (TNF)-alpha in patients with IGM. Read More

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http://dx.doi.org/10.1007/s10067-020-04925-8DOI Listing

Calcium signalling in mammalian cell lines expressing wild type and mutant human α1-Antitrypsin.

Sci Rep 2019 11 21;9(1):17293. Epub 2019 Nov 21.

Centre for Respiratory Biology, UCL Respiratory, Rayne Building, University College London, 5 University Street, London, WC1E 6JF, UK.

A possible role for calcium signalling in the autosomal dominant form of dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), has been proposed, which may point towards a mechanism by which cells could sense and respond to the accumulation of mutant serpin polymers in the endoplasmic reticulum (ER). We therefore explored possible defects in Ca-signalling, which may contribute to the pathology associated with another serpinopathy, α-antitrypsin (AAT) deficiency. Using CHO K1 cell lines stably expressing a wild type human AAT (MAAT) and a disease-causing polymer-forming variant (ZAAT) and the truncated variant (NHK AAT), we measured basal intracellular free Ca, its responses to thapsigargin (TG), an ER Ca-ATPase blocker, and store-operated Ca-entry (SOCE). Read More

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http://dx.doi.org/10.1038/s41598-019-53535-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872872PMC
November 2019

Treatment with inhaled α1-antitrypsin: a square peg in a round hole?

Eur Respir J 2019 11 21;54(5). Epub 2019 Nov 21.

Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), Barcelona, Spain

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http://dx.doi.org/10.1183/13993003.01894-2019DOI Listing
November 2019

Regulation of reticulophagy by the N-degron pathway.

Autophagy 2020 02 27;16(2):373-375. Epub 2019 Nov 27.

Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, Korea.

Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. Read More

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http://dx.doi.org/10.1080/15548627.2019.1695402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984588PMC
February 2020

Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in Knockout Mice.

Cells 2019 11 9;8(11). Epub 2019 Nov 9.

Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, D-52074 Aachen, Germany.

The presence of the homozygous 'Pi*Z' variant of alpha-1 antitrypsin (AAT) ('Pi*ZZ' genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene () as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. Read More

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http://dx.doi.org/10.3390/cells8111415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912453PMC
November 2019

Geographic distribution of chronic obstructive pulmonary disease prevalence in Africa, Asia and Australasia.

Int J Tuberc Lung Dis 2019 10;23(10):1100-1106

Pneumology Department, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), Barcelona, CIBER de Enfermedades Respiratorias (CIBERES). Barcelona, Spain.

To visualise spatial data on chronic obstructive pulmonary disease (COPD) prevalence in Africa, Asia and Australasia using a Geographic Information System (GIS) inverse distance weighted (IDW) interpolation technique. Prevalence rates from population surveys on individuals aged ≥40, with spirometry-confirmed COPD, were searched systematically. The prevalence observed in 59 selected surveys and the geographic coordinates of the places where they were conducted informed a GIS computer programme. Read More

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http://dx.doi.org/10.5588/ijtld.19.0015DOI Listing
October 2019
1 Read

Comparison of the liquid and lyophilized formulations of Prolastin®-C for Alpha-Antitrypsin deficiency: Biochemical characteristics, pharmacokinetics, safety and neoantigenicity in rabbits.

Biologicals 2019 Nov 12;62:77-84. Epub 2019 Sep 12.

Grifols Bioscience Research Group, 85 TW Alexander Drive, Research Triangle Park, NC, 27709, USA.

Multiple analytical and preclinical studies were performed to compare the biochemical characteristics, pharmacokinetics (PK), safety and neoantigenicity of a new 5% liquid formulation of Alpha-1 Proteinase Inhibitor (Liquid A1PI, Prolastin®-C Liquid) with the lyophilized version (Lyophilized A1PI, Prolastin®-C). Liquid A1PI and Lyophilized A1PI had similar average mass (~52 kDa), and both forms exhibited glycoform patterns consistent with the known banding pattern of A1PI (dominated by the M6 and M4 bands, including deconvoluted masses). Both Liquid A1PI and Lyophilized A1PI yielded average percent purity values ranging from 96% to 99% and had active content ranging from 53  mg/mL to 59  mg/mL. Read More

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http://dx.doi.org/10.1016/j.biologicals.2019.09.002DOI Listing
November 2019
2 Reads
1.209 Impact Factor

Exome Sequencing Reveals Immune Genes as Susceptibility Modifiers in Individuals with α-Antitrypsin Deficiency.

Sci Rep 2019 09 11;9(1):13088. Epub 2019 Sep 11.

Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Padova, Italy.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated to early onset emphysema, mainly imputable to Pi*ZZ genotype. In spite of the serious potential effects, many AATD individuals do not develop emphysema. To identify genes/variants potentially involved in emphysema development we studied 4 AATD families. Read More

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http://www.nature.com/articles/s41598-019-49409-1
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http://dx.doi.org/10.1038/s41598-019-49409-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739380PMC
September 2019
2 Reads

Efficacy and safety of inhaled α1-antitrypsin in patients with severe α1-antitrypsin deficiency and frequent exacerbations of COPD.

Eur Respir J 2019 11 21;54(5). Epub 2019 Nov 21.

Queen Elizabeth Hospital, Birmingham, UK.

Patients with inherited α1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently experience exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Read More

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http://dx.doi.org/10.1183/13993003.00673-2019DOI Listing
November 2019
3 Reads

Adipose Mesenchymal Extracellular Vesicles as Alpha-1-Antitrypsin Physiological Delivery Systems for Lung Regeneration.

Cells 2019 08 23;8(9). Epub 2019 Aug 23.

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.

Accumulating evidence shows that Mesenchymal Stem/Stromal Cells (MSCs) exert their therapeutic effects by the release of secretome, made of both soluble proteins and nano/microstructured extracellular vesicles (EVs). In this work, for the first time, we proved by a proteomic investigation that adipose-derived (AD)-MSC-secretome contains alpha-1-antitrypsin (AAT), the main elastase inhibitor in the lung, 72 other proteins involved in protease/antiprotease balance, and 46 proteins involved in the response to bacteria. By secretome fractionation, we proved that AAT is present both in the soluble fraction of secretome and aggregated and/or adsorbed on the surface of EVs, that can act as natural carriers promoting AAT in vivo stability and activity. Read More

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http://dx.doi.org/10.3390/cells8090965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770759PMC
August 2019
2 Reads

A specific proteinase 3 activity footprint in α-antitrypsin deficiency.

ERJ Open Res 2019 Jul 5;5(3). Epub 2019 Aug 5.

University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK.

α-Antitrypsin (α-AT) deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase (NE) has long been considered the enzyme responsible. However, proteinase 3 (PR3) also produces the pathological features of chronic obstructive pulmonary disease (COPD), is present in the same granules in the neutrophil and is inhibited after NE. Read More

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http://dx.doi.org/10.1183/23120541.00095-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6680069PMC
July 2019
4 Reads

The N-Degron Pathway Mediates ER-phagy.

Mol Cell 2019 09 30;75(5):1058-1072.e9. Epub 2019 Jul 30.

Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; Protech, Yongeon 103 Daehangno, Jongno-gu, Seoul 110-799, Republic of Korea; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea. Electronic address:

The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. Read More

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http://dx.doi.org/10.1016/j.molcel.2019.06.028DOI Listing
September 2019
4 Reads

Design and characterization of α1-antitrypsin variants for treatment of contact system-driven thromboinflammation.

Blood 2019 11;134(19):1658-1669

Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The contact system produces the inflammatory peptide bradykinin and contributes to experimental thrombosis. C1 esterase-inhibitor (C1INH) deficiency or gain-of-function mutations in factor XII (FXII) cause hereditary angioedema, a life-threatening tissue swelling disease. C1INH is a relatively weak contact system enzyme inhibitor. Read More

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http://dx.doi.org/10.1182/blood.2019000481DOI Listing
November 2019
7 Reads

Mesenchymal stem/stromal cell secretome for lung regeneration: The long way through "pharmaceuticalization" for the best formulation.

J Control Release 2019 09 18;309:11-24. Epub 2019 Jul 18.

Department of Drug Sciences, University of Pavia, Viale Taramelli 12, Pavia, Italy; PharmaExceed srl, 27100 Pavia, Italy.

Pulmonary acute and chronic diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and pulmonary hypertension, are considered to be major health issues worldwide. Cellular therapies with Mesenchymal Stem Cells (MSCs) offer a new therapeutic approach for chronic and acute lung diseases related to their anti-inflammatory, immunomodulatory, regenerative, pro-angiogenic and anti-fibrotic properties. Such therapeutic effects can be attributed to MSC-secretome, made of free soluble proteins and extracellular vesicles (EVs). Read More

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http://dx.doi.org/10.1016/j.jconrel.2019.07.022DOI Listing
September 2019
3 Reads

Pitfalls and caveats in α1-antitrypsin deficiency testing: a guide for clinicians.

Lancet Respir Med 2019 12 16;7(12):1059-1067. Epub 2019 Jul 16.

Irish Centre for Genetic Lung Disease, Royal College of Surgeons in Ireland, Dublin, Ireland; Department of Medicine, Beaumont Hospital, Dublin, Ireland.

α1-antitrypsin deficiency (AATD) remains the only readily identified genetic cause of chronic obstructive pulmonary disease (COPD). Furthermore, there is growing evidence that even a moderate deficiency increases the risk of lung disease among smokers. Despite these facts, the uptake of testing for AATD in at-risk populations remains low for many reasons, and a lack of clarity among clinicians regarding the most appropriate diagnostic techniques presents a major deterrent. Read More

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http://dx.doi.org/10.1016/S2213-2600(19)30141-9DOI Listing
December 2019
3 Reads

SERPINA1 gene polymorphisms in a population-based ALSPAC cohort.

Pediatr Pulmonol 2019 09 12;54(9):1474-1478. Epub 2019 Jul 12.

Department of Paediatric Pulmonology, Clinic of Children's Diseases, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.

Background: There is an association between persistent preschool wheezing phenotypes and school-age asthma. These wheezing/asthma phenotypes likely represent clinical entities having specific genetic risk factors. The SERPINA1 gene encodes α -antitrypsin (AAT), and mutations in the gene are important in the pathophysiology of pulmonary diseases. Read More

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http://dx.doi.org/10.1002/ppul.24422DOI Listing
September 2019
4 Reads

DEFI-ALFA: The French key to the alpha1 mystery?

Liver Int 2019 06;39(6):1019-1021

Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network (ERN) "Rare Liver" and the European Association for the Study of the Liver (EASL) Registry Group "Alpha1-Liver", Aachen, Germany.

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http://dx.doi.org/10.1111/liv.14064DOI Listing
June 2019
6 Reads

Liver Fibrosis and Metabolic Alterations in Adults With alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation.

Gastroenterology 2019 09 20;157(3):705-719.e18. Epub 2019 May 20.

Coordinating Center for Alpha1-Antitrypsin Deficiency-Related Liver Disease of the European Reference Network "Rare Liver" and the European Association for the Study of the Liver Registry Group "Alpha1-Liver," University Hospital Aachen, Aachen, Germany; Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany. Electronic address:

Background & Aims: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S00165085194089
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http://dx.doi.org/10.1053/j.gastro.2019.05.013DOI Listing
September 2019
43 Reads

Targeting the site encoded by SERPINA1*E342K for treating alpha-1 antitrypsin deficiency-associated liver diseases.

FEBS Lett 2019 07 6;593(14):1849-1862. Epub 2019 Jun 6.

Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA.

Alpha1-antitrypsin (AAT) deficiency predisposes individuals to emphysema and liver diseases such as cirrhosis and hepatocellular carcinoma. The deficiency results from mutations in the SERPIN1A gene encoding AAT molecules that cause hepatotoxic retention within the endoplasmic reticulum. Since the E342K mutation is the basis for destabilization leading to lung and liver pathologies, we used the crystal structure of the mutated AAT as the basis for molecular docking selection of candidate compounds that may bind and stabilize the 342K structural pocket. Read More

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http://dx.doi.org/10.1002/1873-3468.13452DOI Listing
July 2019
10 Reads

A combined in silico and in vitro study on mouse Serpina1a antitrypsin-deficiency mutants.

Sci Rep 2019 05 16;9(1):7486. Epub 2019 May 16.

Research Group Translational Hepatology and Stem Cell Biology, Cluster of Excellence REBIRTH, Hannover Medical School, Hannover, 30625, Germany.

Certain point-mutations in the human SERPINA1-gene can cause severe α1-antitrypsin-deficiency (A1AT-D). Affected individuals can suffer from loss-of-function lung-disease and from gain-of-function liver-disease phenotypes. However, age of onset and severity of clinical appearance is heterogeneous amongst carriers, suggesting involvement of additional genetic and environmental factors. Read More

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http://www.nature.com/articles/s41598-019-44043-3
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http://dx.doi.org/10.1038/s41598-019-44043-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522476PMC
May 2019
12 Reads

A transgenic zebrafish model of hepatocyte function in human Z α1-antitrypsin deficiency.

Biol Chem 2019 11;400(12):1603-1616

Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne 3800, Victoria, Australia.

In human α1-antitrypsin deficiency, homozygous carriers of the Z (E324K) mutation in the gene SERPINA1 have insufficient circulating α1-antitrypsin and are predisposed to emphysema. Misfolding and accumulation of the mutant protein in hepatocytes also causes endoplasmic reticulum stress and underpins long-term liver damage. Here, we describe transgenic zebrafish (Danio rerio) expressing the wildtype or the Z mutant form of human α1-antitrypsin in hepatocytes. Read More

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http://dx.doi.org/10.1515/hsz-2018-0391DOI Listing
November 2019
4 Reads
3.268 Impact Factor

Geographic distribution of COPD prevalence in the world displayed by Geographic Information System maps.

Eur Respir J 2019 07 18;54(1). Epub 2019 Jul 18.

Pneumology Dept, Hospital Universitari Vall d'Hebron/Vall d'Hebron Research Institute (VHIR), CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain

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http://dx.doi.org/10.1183/13993003.00610-2019DOI Listing
July 2019
6 Reads

Diagnosis and management of α-antitrypsin deficiency in Europe: an expert survey.

ERJ Open Res 2019 Feb 11;5(1). Epub 2019 Mar 11.

Dept of Respiratory Medicine, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland.

Despite recent improvements, α-antitrypsin deficiency (AATD) remains a rarely diagnosed and treated condition. To assess the variability of AATD diagnosis/treatment in Europe, and to evaluate clinicians' views on methods to optimise management, specialist AATD clinicians were invited to complete a web-based survey. Surveys were completed by 15 physicians from 14 centres in 13 European countries. Read More

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http://dx.doi.org/10.1183/23120541.00171-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409083PMC
February 2019
9 Reads

Reactive centre loop dynamics and serpin specificity.

Sci Rep 2019 03 7;9(1):3870. Epub 2019 Mar 7.

Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Victoria, 3800, Australia.

Serine proteinase inhibitors (serpins), typically fold to a metastable native state and undergo a major conformational change in order to inhibit target proteases. However, conformational lability of the native serpin fold renders them susceptible to misfolding and aggregation, and underlies misfolding diseases such as α-antitrypsin deficiency. Serpin specificity towards its protease target is dictated by its flexible and solvent exposed reactive centre loop (RCL), which forms the initial interaction with the target protease during inhibition. Read More

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http://dx.doi.org/10.1038/s41598-019-40432-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405850PMC
March 2019
8 Reads

Modulation of calreticulin expression reveals a novel exosome-mediated mechanism of Z variant α-antitrypsin disposal.

J Biol Chem 2019 04 4;294(16):6240-6252. Epub 2019 Mar 4.

From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine,

α-Antitrypsin deficiency (AATD) is an inherited disease characterized by emphysema and liver disease. AATD is most often caused by a single amino acid substitution at position 342 in the mature protein, resulting in the Z mutation of the AAT gene (ZAAT). This substitution is associated with misfolding and accumulation of ZAAT in the endoplasmic reticulum (ER) of hepatocytes, causing a toxic gain of function. Read More

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http://dx.doi.org/10.1074/jbc.RA118.006142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484112PMC
April 2019
7 Reads

Blood monocyte profiles in COPD patients with PiMM and PiZZ α1-antitrypsin.

Respir Med 2019 03 6;148:60-62. Epub 2019 Feb 6.

Department of Respiratory Medicine, Hannover Medical School, Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Member of German Centre for Lung Research (DZL), Hannover, Germany. Electronic address:

Human blood monocytes are divided into populations based on the differential expression of CD14 and CD16 receptors: CD14  CD16(classical), CD14  CD16  (intermediate), and CD14CD16 (non-classical). Given their functional differences and their role in pathogenesis of chronic obstructive pulmonary disease (COPD), monocyte profiling is of clinical interest. Here we investigated blood monocyte subsets in clinically stable COPD patients with alpha1-antitrypsin (AAT) deficiency (PiZZ, n = 7) and with normal AAT variant (PiMM, n = 7). Read More

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http://dx.doi.org/10.1016/j.rmed.2019.02.001DOI Listing
March 2019
6 Reads

Emphysema: looking beyond alpha-1 antitrypsin deficiency.

Expert Rev Respir Med 2019 04 22;13(4):381-397. Epub 2019 Feb 22.

b Department of Respiratory Medicine , Maastricht University Medical Center , Maastricht , The Netherlands.

Introduction: Distinct pathologies can cause chronic obstructive pulmonary disease (COPD). Emphysema is a COPD-phenotype characterized by destruction of lung parenchyma. Alpha-1 antitrypsin deficiency (AATD) is a genetic cause of emphysema, whereas smoking is the most important risk factor of non-AATD emphysema. Read More

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http://dx.doi.org/10.1080/17476348.2019.1580575DOI Listing
April 2019
32 Reads

Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides.

Nat Biotechnol 2019 02 28;37(2):133-138. Epub 2019 Jan 28.

Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany.

Site-directed RNA editing might provide a safer or more effective alternative to genome editing in certain clinical scenarios. Until now, RNA editing has relied on overexpression of exogenous RNA editing enzymes or of endogenous human ADAR (adenosine deaminase acting on RNA) enzymes. Here we describe the engineering of chemically optimized antisense oligonucleotides that recruit endogenous human ADARs to edit endogenous transcripts in a simple and programmable way, an approach we call RESTORE (recruiting endogenous ADAR to specific transcripts for oligonucleotide-mediated RNA editing). Read More

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http://www.nature.com/articles/s41587-019-0013-6
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http://dx.doi.org/10.1038/s41587-019-0013-6DOI Listing
February 2019
11 Reads

An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z.

PLoS One 2019 23;14(1):e0209748. Epub 2019 Jan 23.

Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343872PMC
November 2019
21 Reads
3.234 Impact Factor

FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice.

Arterioscler Thromb Vasc Biol 2019 03;39(3):387-401

From the Translational Laboratories in Genetic Medicine, A*STAR Institute, and Yong Loo Lin School of Medicine, National University of Singapore (G.K.Y., C.R., K.A., D.C.M., M.C., Z.W., A.L.J.T., L.T.-M., R.C., T.C., R.R.S.).

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Read More

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https://www.ahajournals.org/doi/10.1161/ATVBAHA.118.311903
Publisher Site
http://dx.doi.org/10.1161/ATVBAHA.118.311903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393193PMC
March 2019
42 Reads