Database : MEDLINE
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[PMID]: 29524647
[Au] Autor:Zhao M; Wu J; Li X; Gao Y
[Ad] Address:Department of Laboratory Medicine, Beijing Hospital, National Center of Gerontology, Beijing, China; Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
[Ti] Title:Urinary candidate biomarkers in an experimental autoimmune myocarditis rat model.
[So] Source:J Proteomics;, 2018 Mar 07.
[Is] ISSN:1876-7737
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Urine is a better source than plasma for biomarker studies, as it can accumulate all changes in the body. Various candidate urinary biomarkers of physiological condition, kidney disease and even brain dysfunction, have been detected in urine; however, urine has rarely been used to reflect cardiac diseases. In this study, urine at day 0, 14, 21 and 28 were collected from the myosin-induced autoimmune myocarditis rat models. The candidate urinary biomarkers were then characterized using the isobaric tandem mass tag labeling approach coupled with offline two-dimensional reverse-phase liquid chromatography and high-resolution mass spectrometry. Compared with controls, forty-six urinary proteins were significantly changed in the myocarditis rats; among them, ten had previously been associated with myocarditis, twelve corresponding gene products had annotated as mainly cardiovascular network genes by the Ingenuity Pathway Analysis, four urinary proteins were validated by western blot, thirteen were reported in previous urine proteome studies of other diseases and twenty-six were reported the first time to be related to myocarditis. SIGNIFICANCE: This is the first study to use isobaric tandem mass tag labeling approach in the urine proteome analysis of experimental autoimmune myocarditis. These findings may provide clues for the pathogenesis of myocarditis. And the study showed that urine can be a good source of myocarditis biomarkers.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  2 / 224544 MEDLINE  
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[PMID]: 29510922
[Au] Autor:Ku E; Vittinghoff E; Jacobs DR; Lewis CE; Allen NB; Bibbins-Domingo K; Shlipak M; Kramer H; Peralta CA
[Ad] Address:Division of Nephrology, Department of Medicine, University of California, San Francisco, CA; Division of Pediatric Nephrology, Department of Pediatrics, University of California, San Francisco, CA. Electronic address: elaine.ku@ucsf.edu.
[Ti] Title:Changes in Blood Pressure During Young Adulthood and Subsequent Kidney Function Decline: Findings From the Coronary Artery Risk Development in Young Adulthood (CARDIA) Study.
[So] Source:Am J Kidney Dis;, 2018 Mar 03.
[Is] ISSN:1523-6838
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Many studies have focused on the association between a single blood pressure (BP) measurement and risk for adverse outcomes. However, the association of BP trajectories during young adulthood with subsequent decline in kidney function has not been well defined. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 3,429 participants in the Coronary Artery Risk Development in Young Adulthood (CARDIA) Study enrolled between the ages of 18 and 30 years. PREDICTORS: BP slope during the first 10 years of participation in CARDIA, derived from linear mixed models incorporating all repeated BP measures. OUTCOME: Decline in estimated glomerular filtration rate (eGFR) during the interval between years 10 and 20 of CARDIA participation using cystatin C measured at years 10, 15, and 20. RESULTS: Mean age of CARDIA participants at year 0 was 25.1 years, 56% were women, and 53% were white. Every 10-mmHg higher level of systolic (SBP) and diastolic BP (DBP) in year 10 was associated with change in eGFR of -0.09 (95% CI, -0.13 to -0.06) and -0.07 (95% CI, -0.12 to -0.03) mL/min/1.73m per year, respectively. Every 10-mmHg increase in SBP slope between years 0 and 10 was associated with a subsequent -0.52 (95% CI, -1.02 to -0.03) mL/min/1.73m per year change in kidney function after adjustment for comorbid conditions and SBP at year 10. Similarly, every 10-mmHg increase in DBP slope between years 0 and 10 was associated with a subsequent change in kidney function of -0.65 (95% CI, -1.23 to -0.07) mL/min/1.73m per year, after adjustment for comorbid conditions and DBP in year 10. LIMITATIONS: Observational design. CONCLUSIONS: During young adulthood, increasing SBP and DBP are associated with a higher rate of subsequent kidney function decline, independent of BP measured at the beginning of eGFR assessment.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:Publisher

  3 / 224544 MEDLINE  
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[PMID]: 29467330
[Au] Autor:Christov M; Clark AR; Corbin B; Hakroush S; Rhee EP; Saito H; Brooks D; Hesse E; Bouxsein M; Galjart N; Jung JY; Mundel P; Jüppner H; Weins A; Greka A
[Ad] Address:Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
[Ti] Title:Inducible podocyte-specific deletion of CTCF drives progressive kidney disease and bone abnormalities.
[So] Source:JCI Insight;3(4), 2018 Feb 22.
[Is] ISSN:2379-3708
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Progressive chronic kidney diseases (CKDs) are on the rise worldwide. However, the sequence of events resulting in CKD progression remain poorly understood. Animal models of CKD exploring these issues are confounded by systemic toxicities or surgical interventions to acutely induce kidney injury. Here we report the generation of a CKD mouse model through the inducible podocyte-specific ablation of an essential endogenous molecule, the chromatin structure regulator CCCTC-binding factor (CTCF), which leads to rapid podocyte loss (iCTCFpod-/-). As a consequence, iCTCFpod-/- mice develop severe progressive albuminuria, hyperlipidemia, hypoalbuminemia, and impairment of renal function, and die within 8-10 weeks. CKD progression in iCTCFpod-/- mice leads to high serum phosphate and elevations in fibroblast growth factor 23 (FGF23) and parathyroid hormone that rapidly cause bone mineralization defects, increased bone resorption, and bone loss. Dissection of the timeline leading to glomerular pathology in this CKD model led to the surprising observation that podocyte ablation and the resulting glomerular filter destruction is sufficient to drive progressive CKD and osteodystrophy in the absence of interstitial fibrosis. This work introduces an animal model with significant advantages for the study of CKD progression, and it highlights the need for podocyte-protective strategies for future kidney therapeutics.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:Publisher

  4 / 224544 MEDLINE  
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[PMID]: 29425932
[Au] Autor:Noh MR; Woo CH; Park MJ; In Kim J; Park KM
[Ad] Address:Department of Anatomy and BK21 Plus, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Junggu, Daegu 41944, Republic of Korea.
[Ti] Title:Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption.
[So] Source:Biochim Biophys Acta;1864(5 Pt A):1634-1641, 2018 Feb 07.
[Is] ISSN:0006-3002
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Fibrosis is an undesirable consequence of injury and a critical problem in many diseases. Recent studies have demonstrated an association of C/EBP homologous protein (CHOP) with fibrosis. We investigated the mechanism of CHOP in kidney fibrosis progression after unilateral ureteral obstruction (UUO) using Chop gene-deleted (Chop ) mice and their wild-type littermates (Chop ). UUO-induced kidney fibrosis was reduced in the Chop than Chop mice. After UUO, CHOP expression was detected in the cytosol and nucleus of distal tubule cells and collecting duct cells of the kidney. UUO formed the autophagosome and increased the expression of autophagy proteins, Beclin-1, LC3-I and II, and p62 in the kidneys. These UUO-induced changes were significantly reduced in Chop mice. Furthermore, Chop gene deletion attenuated mitochondrial fragmentation with lower expression of Fis-1, a mitochondrial fission protein, but higher expression of Opa-1, a mitochondrial fusion protein, than that seen in the wild-type mice. UUO disrupted the microtubule, which is involved in autophagosome formation, and this disruption was milder in the Chop than Chop mouse kidney, with less reduction of histone deacetylase 6 and α­tubulin acetyl transferase, which acetylates tubulin, a component of the microtubule. After UUO, apoptosis, a consequence of autophagy and mitochondrial damage, was reduced in the Chop mouse kidney cells than in Chop mice. Thus, the ablation of Chop attenuates renal fibrosis, accompanied by reduced autophagy, mitochondrial fragmentation, microtubule disruption, and apoptosis. Overall, these results suggest that CHOP plays a critical role in the progression of kidney fibrosis, likely through regulation of autophagy and apoptosis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  5 / 224544 MEDLINE  
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[PMID]: 29412048
[Au] Autor:Caldwell RW; Rodriguez PC; Toque HA; Narayanan SP; Caldwell RB
[Ad] Address:Department of Pharmacology & Toxicology, Vision Discovery Institute, Department of Medicine-Hematology and Oncology, Department of Occupational Therapy, School of Allied Health Sciences, and Vascular Biology Center, Medical College of Georgia, Augusta University , Augusta, Georgia ; and VA Medic
[Ti] Title:Arginase: A Multifaceted Enzyme Important in Health and Disease.
[So] Source:Physiol Rev;98(2):641-665, 2018 Apr 01.
[Is] ISSN:1522-1210
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The arginase enzyme developed in early life forms and was maintained during evolution. As the last step in the urea cycle, arginase cleaves l-arginine to form urea and l-ornithine. The urea cycle provides protection against excess ammonia, while l-ornithine is needed for cell proliferation, collagen formation, and other physiological functions. In mammals, increases in arginase activity have been linked to dysfunction and pathologies of the cardiovascular system, kidney, and central nervous system and also to dysfunction of the immune system and cancer. Two important aspects of the excessive activity of arginase may be involved in diseases. First, overly active arginase can reduce the supply of l-arginine needed for the production of nitric oxide (NO) by NO synthase. Second, too much l-ornithine can lead to structural problems in the vasculature, neuronal toxicity, and abnormal growth of tumor cells. Seminal studies have demonstrated that increased formation of reactive oxygen species and key inflammatory mediators promote this pathological elevation of arginase activity. Here, we review the involvement of arginase in diseases affecting the cardiovascular, renal, and central nervous system and cancer and discuss the value of therapies targeting the elevated activity of arginase.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1152/physrev.00037.2016

  6 / 224544 MEDLINE  
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Martins, Regina Maria Bringel
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[PMID]: 29408465
[Au] Autor:de Oliveira JMNS; Freitas NR; Teles SA; Bottino FO; Lemos AS; de Oliveira JM; de Paula V; Pinto MA; Martins RMB
[Ad] Address:Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.
[Ti] Title:Prevalence of hepatitis E virus RNA and antibodies in a cohort of kidney transplant recipients in Central Brazil.
[So] Source:Int J Infect Dis;69:41-43, 2018 Feb 10.
[Is] ISSN:1878-3511
[Cp] Country of publication:Canada
[La] Language:eng
[Ab] Abstract:OBJECTIVE: To assess the prevalence of hepatitis E virus (HEV) RNA and antibodies among kidney transplant recipients (KTR) in Central Brazil. The presence of chronic HEV infection was also investigated. METHODS: A cohort study was conducted among 316 KTR treated at a referral center for kidney transplantation in Goiânia, Brazil. All serum samples were tested for the presence of HEV RNA (real-time PCR) and anti-HEV IgG/IgM (ELISA). Anti-HEV-positive samples were confirmed using an immunoblot test. HEV chronicity was investigated in a subgroup of patients with elevated alanine aminotransferase (ALT >40IU/l) through HEV RNA detection in additional serum samples collected 3 and 6 months apart. RESULTS: A seroprevalence of 2.5% (95% confidence interval 1.2-5.1%) was found for anti-HEV IgG. There was no difference in characteristics between the anti-HEV IgG seropositive and seronegative KTR groups. Anti-HEV IgM was detected in only one patient (0.3%). All KTR were negative for HEV RNA. CONCLUSIONS: These results show that HEV infection is infrequent in KTR in Central Brazil, with low seroprevalence rates of past and recent infection, and also an absence of active and chronic HEV infections.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  7 / 224544 MEDLINE  
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[PMID]: 29360619
[Au] Autor:Whyte MP; Coburn SP; Ryan LM; Ericson KL; Zhang F
[Ad] Address:Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, MO 63110, USA. Electronic address
[Ti] Title:Hypophosphatasia: Biochemical hallmarks validate the expanded pediatric clinical nosology.
[So] Source:Bone;110:96-106, 2018 Jan 31.
[Is] ISSN:1873-2763
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Hypophosphatasia (HPP) is the inborn-error-of-metabolism due to loss-of-function mutation(s) of the ALPL (TNSALP) gene that encodes the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). TNSALP represents a family of cell-surface phosphohydrolases differing by post-translational modification that is expressed especially in the skeleton, liver, kidney, and developing teeth. Thus, the natural substrates of TNSALP accumulate extracellularly in HPP including inorganic pyrophosphate (PPi), a potent inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B . The superabundance of extracellular PPi regularly causes tooth loss, and when sufficiently great can lead to rickets or osteomalacia. Sometimes diminished hydrolysis of PLP engenders vitamin B -dependent seizures in profoundly affected babies. Autosomal dominant and autosomal recessive inheritance from among >340 ALPL mutations identified to date, typically missense and located throughout the gene, largely explains the remarkably wide-ranging severity of HPP, greatest of all skeletal diseases. In 2015, our demographic, clinical, and DXA findings acquired over 25 years from 173 children and adolescents with HPP validated and expanded the clinical nosology for pediatric patients to include according to increasing severity "odonto" HPP, "mild childhood" HPP, "severe childhood" HPP, "infantile" HPP, and "perinatal" HPP. Herein, we assessed this expanded nosology using biochemical hallmarks of HPP. We evaluated exclusively data from the 165 preteenage HPP patients in this cohort to exclude potential effects from physiological changes in TNSALP levels across puberty. All patients had subnormal serum total and bone-specific ALP and elevated plasma PLP, and nearly all had excessive urinary PPi excretion. Only the PLP levels were unchanged across puberty. Mean levels of all four biomarkers correlated with HPP severity ranked according to the HPP nosology, but the data overlapped among all four patient groups. Hence, these four biochemical hallmarks represent both a sensitive and reliable tool for diagnosing children with HPP. Furthermore, the hallmarks validate our expanded clinical nosology for pediatric HPP that, with limitations, is an improved framework for conceptualizing and working with this disorder's remarkably broad-ranging severity.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  8 / 224544 MEDLINE  
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Clinical Trials Registry
Clinical Trials Registry
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[PMID]: 29297076
[Au] Autor:Feldman TE; Reardon MJ; Rajagopal V; Makkar RR; Bajwa TK; Kleiman NS; Linke A; Kereiakes DJ; Waksman R; Thourani VH; Stoler RC; Mishkel GJ; Rizik DG; Iyer VS; Gleason TG; Tchétché D; Rovin JD; Buchbinder M; Meredith IT; Götberg M; Bjursten H; Meduri C; Salinger MH; Allocco DJ; Dawkins KD
[Ad] Address:Evanston Hospital Cardiology Division, Northshore University Health System, Evanston, Illinois.
[Ti] Title:Effect of Mechanically Expanded vs Self-Expanding Transcatheter Aortic Valve Replacement on Mortality and Major Adverse Clinical Events in High-Risk Patients With Aortic Stenosis: The REPRISE III Randomized Clinical Trial.
[So] Source:JAMA;319(1):27-37, 2018 01 02.
[Is] ISSN:1538-3598
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Importance: Transcatheter aortic valve replacement (TAVR) is established for selected patients with severe aortic stenosis. However, limitations such as suboptimal deployment, conduction disturbances, and paravalvular leak occur. Objective: To evaluate if a mechanically expanded valve (MEV) is noninferior to an approved self-expanding valve (SEV) in high-risk patients with aortic stenosis undergoing TAVR. Design, Setting, and Participants: The REPRISE III trial was conducted in 912 patients with high or extreme risk and severe, symptomatic aortic stenosis at 55 centers in North America, Europe, and Australia between September 22, 2014, and December 24, 2015, with final follow-up on March 8, 2017. Interventions: Participants were randomized in a 2:1 ratio to receive either an MEV (n = 607) or an SEV (n = 305). Main Outcomes and Measures: The primary safety end point was the 30-day composite of all-cause mortality, stroke, life-threatening or major bleeding, stage 2/3 acute kidney injury, and major vascular complications tested for noninferiority (margin, 10.5%). The primary effectiveness end point was the 1-year composite of all-cause mortality, disabling stroke, and moderate or greater paravalvular leak tested for noninferiority (margin, 9.5%). If noninferiority criteria were met, the secondary end point of 1-year moderate or greater paravalvular leak was tested for superiority in the full analysis data set. Results: Among 912 randomized patients (mean age, 82.8 [SD, 7.3] years; 463 [51%] women; predicted risk of mortality, 6.8%), 874 (96%) were evaluable at 1 year. The primary safety composite end point at 30 days occurred in 20.3% of MEV patients and 17.2% of SEV patients (difference, 3.1%; Farrington-Manning 97.5% CI, -∞ to 8.3%; P = .003 for noninferiority). At 1 year, the primary effectiveness composite end point occurred in 15.4% with the MEV and 25.5% with the SEV (difference, -10.1%; Farrington-Manning 97.5% CI, -∞ to -4.4%; P<.001 for noninferiority). The 1-year rates of moderate or severe paravalvular leak were 0.9% for the MEV and 6.8% for the SEV (difference, -6.1%; 95% CI, -9.6% to -2.6%; P < .001). The superiority analysis for primary effectiveness was statistically significant (difference, -10.2%; 95% CI, -16.3% to -4.0%; P < .001). The MEV had higher rates of new pacemaker implants (35.5% vs 19.6%; P < .001) and valve thrombosis (1.5% vs 0%) but lower rates of repeat procedures (0.2% vs 2.0%), valve-in-valve deployments (0% vs 3.7%), and valve malpositioning (0% vs 2.7%). Conclusions and Relevance: Among high-risk patients with aortic stenosis, use of the MEV compared with the SEV did not result in inferior outcomes for the primary safety end point or the primary effectiveness end point. These findings suggest that the MEV may be a useful addition for TAVR in high-risk patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02202434.
[Mh] MeSH terms primary: Aortic Valve Stenosis/surgery
Aortic Valve/surgery
Heart Valve Prosthesis
Transcatheter Aortic Valve Replacement/adverse effects
[Mh] MeSH terms secundary: Aged
Aged, 80 and over
Aortic Valve Stenosis/mortality
Bioprosthesis
Cardiovascular Diseases/etiology
Cardiovascular Diseases/mortality
Female
Follow-Up Studies
Humans
Male
Postoperative Complications/etiology
Prosthesis Design
Risk Factors
Transcatheter Aortic Valve Replacement/methods
Transcatheter Aortic Valve Replacement/mortality
Treatment Outcome
[Pt] Publication type:COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1801
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:180104
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.19132

  9 / 224544 MEDLINE  
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[PMID]: 28747142
[Au] Autor:Zhao Y; Stepto H; Schneider CK
[Ad] Address:1 Division of Advanced Therapies, National Institute for Biological Standards and Control (NIBSC) , Medicines and Health Products Regulatory Agency (MHRA), South Mimms, United Kingdom .
[Ti] Title:Development of the First World Health Organization Lentiviral Vector Standard: Toward the Production Control and Standardization of Lentivirus-Based Gene Therapy Products.
[So] Source:Hum Gene Ther Methods;28(4):205-214, 2017 08.
[Is] ISSN:1946-6544
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Gene therapy is a rapidly evolving field. So far, there have been >2,400 gene therapy products in clinical trials and four products on the market. A prerequisite for producing gene therapy products is ensuring their quality and safety. This requires appropriately controlled and standardized production and testing procedures that result in consistent safety and efficacy. Assuring the quality and safety of lentivirus-based gene therapy products in particular presents a great challenge because they are cell-based multigene products that include viral and therapeutic proteins as well as modified cells. In addition to the continuous refinement of a product, changes in production sites and manufacturing processes have become more and more common, posing challenges to developers regarding reproducibility and comparability of results. This paper discusses the concept of developing a first World Health Organization International Standard, suitable for the standardization of assays and enabling comparison of cross-trial and cross-manufacturing results for this important vector platform. The standard will be expected to optimize the development of gene therapy medicinal products, which is especially important, given the usually orphan nature of the diseases to be treated, naturally hampering reproducibility and comparability of results.
[Mh] MeSH terms primary: Genetic Therapy/standards
Genetic Vectors/standards
Lentivirus/genetics
World Health Organization
[Mh] MeSH terms secundary: Cell Line, Tumor
Genetic Therapy/methods
Genetic Vectors/genetics
HEK293 Cells
Humans
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1801
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[Js] Journal subset:IM
[Da] Date of entry for processing:170728
[St] Status:MEDLINE
[do] DOI:10.1089/hgtb.2017.078

  10 / 224544 MEDLINE  
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[PMID]: 28463571
[Au] Autor:Penaud-Budloo M; Lecomte E; Guy-Duché A; Saleun S; Roulet A; Lopez-Roques C; Tournaire B; Cogné B; Léger A; Blouin V; Lindenbaum P; Moullier P; Ayuso E
[Ad] Address:1 INSERM UMR1089, University of Nantes, Centre Hospitalier Universitaire, Nantes, France.
[Ti] Title:Accurate Identification and Quantification of DNA Species by Next-Generation Sequencing in Adeno-Associated Viral Vectors Produced in Insect Cells.
[So] Source:Hum Gene Ther Methods;28(3):148-162, 2017 06.
[Is] ISSN:1946-6544
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Recombinant adeno-associated viral (rAAV) vectors have proven excellent tools for the treatment of many genetic diseases and other complex diseases. However, the illegitimate encapsidation of DNA contaminants within viral particles constitutes a major safety concern for rAAV-based therapies. Moreover, the development of rAAV vectors for early-phase clinical trials has revealed the limited accuracy of the analytical tools used to characterize these new and complex drugs. Although most published data concerning residual DNA in rAAV preparations have been generated by quantitative PCR, we have developed a novel single-strand virus sequencing (SSV-Seq) method for quantification of DNA contaminants in AAV vectors produced in mammalian cells by next-generation sequencing (NGS). Here, we describe the adaptation of SSV-Seq for the accurate identification and quantification of DNA species in rAAV stocks produced in insect cells. We found that baculoviral DNA was the most abundant contaminant, representing less than 2.1% of NGS reads regardless of serotype (2, 8, or rh10). Sf9 producer cell DNA was detected at low frequency (≤0.03%) in rAAV lots. Advanced computational analyses revealed that (1) baculoviral sequences close to the inverted terminal repeats preferentially underwent illegitimate encapsidation, and (2) single-nucleotide variants were absent from the rAAV genome. The high-throughput sequencing protocol described here enables effective DNA quality control of rAAV vectors produced in insect cells, and is adapted to conform with regulatory agency safety requirements.
[Mh] MeSH terms primary: Dependovirus/genetics
High-Throughput Nucleotide Sequencing/methods
Sequence Analysis, DNA/methods
[Mh] MeSH terms secundary: Animals
Baculoviridae/genetics
DNA Contamination
HEK293 Cells
High-Throughput Nucleotide Sequencing/standards
Humans
Sequence Analysis, DNA/standards
Sf9 Cells
Spodoptera
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1710
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[Js] Journal subset:IM
[Da] Date of entry for processing:170503
[St] Status:MEDLINE
[do] DOI:10.1089/hgtb.2016.185


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