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Article ; Online: Vestronidase alfa: Recombinant human β-glucuronidase as an enzyme replacement therapy for MPS VII.

Cadaoas, Jaclyn / Boyle, Gabrielle / Jungles, Steven / Cullen, Sean / Vellard, Michel / Grubb, Jeffrey H / Jurecka, Agnieszka / Sly, William / Kakkis, Emil

Molecular genetics and metabolism

2020 Volume 130, Issue 1, Page(s) 65–76

Abstract: Mucopolysaccharidosis VII (MPS VII) is a rare lysosomal storage disease characterized by a deficiency in the enzyme β-glucuronidase that has previously been successfully treated in a mouse model with enzyme replacement therapy. Here, we present the ... ...

Abstract	Mucopolysaccharidosis VII (MPS VII) is a rare lysosomal storage disease characterized by a deficiency in the enzyme β-glucuronidase that has previously been successfully treated in a mouse model with enzyme replacement therapy. Here, we present the generation of a novel, highly sialylated version of recombinant human β-glucuronidase (rhGUS), vestronidase alfa, that has high uptake, resulting in an improved enzyme replacement therapy for the treatment of patients with MPS VII. In vitro, vestronidase alfa has 10-fold more sialic acid per mole of rhGUS monomer than a prior rhGUS version (referred to as GUS 43/44) and demonstrated very high affinity at ~1 nM half maximal uptake in human MPS VII fibroblasts. Vestronidase alfa has a longer enzymatic half-life after uptake into fibroblasts compared with other enzymes used as replacement therapy for MPS (40 days vs 3 to 4 days, respectively). In pharmacokinetic and tissue distribution experiments in Sprague-Dawley rats, intravenous administration of vestronidase alfa resulted in higher serum rhGUS levels and enhanced β-glucuronidase activity distributed to target tissues. Weekly intravenous injections of vestronidase alfa (0.1 mg/kg to 20 mg/kg) in a murine model of MPS VII demonstrated efficient enzyme delivery to all tissues, including bone and brain, as well as reduced lysosomal storage of glycosaminoglycans (GAGs) in a dose-dependent manner, resulting in increased survival after 8 weeks of treatment. Vestronidase alfa was well-tolerated and demonstrated no toxicity at concentrations that reached 5-times the proposed clinical dose. In a first-in-human phase 1/2 clinical trial, a dose-dependent reduction in urine GAG levels was sustained over 38 weeks of treatment with vestronidase alfa. Together, these results support the therapeutic potential of vestronidase alfa as an enzyme replacement therapy for patients with MPS VII.
MeSH term(s)	Administration, Intravenous ; Adult ; Animals ; CHO Cells ; Child ; Cricetulus ; Enzyme Replacement Therapy/methods ; Female ; Fibroblasts/metabolism ; Glucuronidase/administration & dosage ; Glucuronidase/blood ; Glucuronidase/genetics ; Glucuronidase/metabolism ; Glucuronidase/pharmacokinetics ; Glycosaminoglycans/metabolism ; Glycosaminoglycans/urine ; Humans ; Lysosomes/enzymology ; Lysosomes/metabolism ; Male ; Mice ; Mice, Transgenic ; Mucopolysaccharidosis VII/enzymology ; Mucopolysaccharidosis VII/therapy ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Tissue Distribution/drug effects
Chemical Substances	Glycosaminoglycans ; Recombinant Proteins ; vestronidase alfa (7XZ4062R17) ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2020-03-06
Publishing country	United States
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2020.02.009
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Article ; Online: Pharmacologic manipulation of lysosomal enzyme transport across the blood-brain barrier.

Urayama, Akihiko / Grubb, Jeffrey H / Sly, William S / Banks, William A

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

2016 Volume 36, Issue 3, Page(s) 476–486

Abstract: The adult blood-brain barrier, unlike the neonatal blood-brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, ...

Abstract	The adult blood-brain barrier, unlike the neonatal blood-brain barrier, does not transport lysosomal enzymes into brain, making enzyme replacement therapy ineffective in treating the central nervous system symptoms of lysosomal storage diseases. However, enzyme transport can be re-induced with alpha-adrenergics. Here, we examined agents that are known to alter the blood-brain barrier transport of large molecules or to induce lysosomal enzyme transport across the blood-brain barrier ((±)epinephrine, insulin, retinoic acid, and lipopolysaccharide) in 2-week-old and adult mice. In 2-week-old adolescent mice, all these pharmacologic agents increased brain and heart uptake of phosphorylated human β-glucuronidase. In 8-week-old adult mice, manipulations with (±)epinephrine, insulin, and retinoic acid were significantly effective on uptake by brain and heart. The increased uptake of phosphorylated human β-glucuronidase was inhibited by mannose 6-phosphate for the agents (±)epinephrine and retinoic acid and by L-NG-nitroarginine methyl ester for the agent lipopolysaccharide in neonatal and adult mice. An in situ brain perfusion study revealed that retinoic acid directly modulated the transport of phosphorylated human β-glucuronidase across the blood-brain barrier. The present study indicates that there are multiple opportunities to at least transiently induce phosphorylated human β-glucuronidase transport at the adult blood-brain barrier.
MeSH term(s)	Animals ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Glucuronidase/administration & dosage ; Glucuronidase/metabolism ; Humans ; Lysosomes/enzymology ; Male ; Mice ; Protein Transport/drug effects ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/metabolism ; Tretinoin/pharmacology
Chemical Substances	Recombinant Proteins ; Tretinoin (5688UTC01R) ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2016-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604628-9
ISSN	1559-7016 ; 0271-678X
ISSN (online)	1559-7016
ISSN	0271-678X
DOI	10.1177/0271678X15614589
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Zs.A 1663: Show issues

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Article ; Online: Feasibility of Coronary Access Following Redo-TAVR for Evolut Failure: A Computed Tomography Simulation Study.

Tang, Gilbert H L / Spencer, Julianne / Rogers, Toby / Grubb, Kendra J / Gleason, Patrick / Gada, Hemal / Mahoney, Paul / Dauerman, Harold L / Forrest, John K / Reardon, Michael J / Blanke, Philipp / Leipsic, Jonathon A / Abdel-Wahab, Mohamed / Attizzani, Guilherme F / Puri, Rishi / Caskey, Michael / Chung, Christine J / Chen, Ying-Hwa / Dudek, Dariusz /

Allen, Keith B / Chhatriwalla, Adnan K / Htun, Wah Wah / Blackman, Daniel J / Tarantini, Giuseppe / Zhingre Sanchez, Jorge / Schwartz, Greta / Popma, Jeffrey J / Sathananthan, Janarthanan

Circulation. Cardiovascular interventions

2023 Volume 16, Issue 11, Page(s) e013238

Abstract: Background: Coronary accessibility following redo-transcatheter aortic valve replacement (redo-TAVR) is increasingly important, particularly in younger low-risk patients. This study aimed to predict coronary accessibility after simulated Sapien-3 ... ...

Abstract	Background: Coronary accessibility following redo-transcatheter aortic valve replacement (redo-TAVR) is increasingly important, particularly in younger low-risk patients. This study aimed to predict coronary accessibility after simulated Sapien-3 balloon-expandable valve implantation within an Evolut supra-annular, self-expanding valve using pre-TAVR computed tomography (CT) imaging. Methods: A total of 219 pre-TAVR CT scans from the Evolut Low-Risk CT substudy were analyzed. Virtual Evolut and Sapien-3 valves were sized using CT-based diameters. Two initial Evolut implant depths were analyzed, 3 and 5 mm. Coronary accessibility was evaluated for 2 Sapien-3 in Evolut implant positions: Sapien-3 outflow at Evolut node 4 and Evolut node 5. Results: With a 3-mm initial Evolut implant depth, suitable coronary access was predicted in 84% of patients with the Sapien-3 outflow at Evolut node 4, and in 31% of cases with the Sapien-3 outflow at Evolut node 5 ( Conclusions: Coronary accessibility after Sapien-3 in Evolut redo-TAVR relates to the initial Evolut implant depth, the Sapien-3 outflow position within the Evolut, and the native annular anatomy. This CT-based quantitative analysis may provide useful information to inform and refine individualized preprocedural CT planning of the initial TAVR and guide lifetime management for future coronary access after redo-TAVR. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02701283.
MeSH term(s)	Humans ; Aortic Valve/diagnostic imaging ; Aortic Valve/surgery ; Transcatheter Aortic Valve Replacement/adverse effects ; Aortic Valve Stenosis/surgery ; Heart Valve Prosthesis ; Feasibility Studies ; Treatment Outcome ; Tomography, X-Ray Computed ; Prosthesis Design
Language	English
Publishing date	2023-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2450797-0
ISSN	1941-7632 ; 1941-7640
ISSN (online)	1941-7632
ISSN	1941-7640
DOI	10.1161/CIRCINTERVENTIONS.123.013238
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Zs.A 6746: Show issues

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Article ; Online: Sinus Tachycardia: a Multidisciplinary Expert Focused Review.

Mayuga, Kenneth A / Fedorowski, Artur / Ricci, Fabrizio / Gopinathannair, Rakesh / Dukes, Jonathan Walter / Gibbons, Christopher / Hanna, Peter / Sorajja, Dan / Chung, Mina / Benditt, David / Sheldon, Robert / Ayache, Mirna B / AbouAssi, Hiba / Shivkumar, Kalyanam / Grubb, Blair P / Hamdan, Mohamed H / Stavrakis, Stavros / Singh, Tamanna / Goldberger, Jeffrey J /

Muldowney, James A S / Belham, Mark / Kem, David C / Akin, Cem / Bruce, Barbara K / Zahka, Nicole E / Fu, Qi / Van Iterson, Erik H / Raj, Satish R / Fouad-Tarazi, Fetnat / Goldstein, David S / Stewart, Julian / Olshansky, Brian

Circulation. Arrhythmia and electrophysiology

2022 Volume 15, Issue 9, Page(s) e007960

Abstract: Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current ... ...

Abstract	Sinus tachycardia (ST) is ubiquitous, but its presence outside of normal physiological triggers in otherwise healthy individuals remains a commonly encountered phenomenon in medical practice. In many cases, ST can be readily explained by a current medical condition that precipitates an increase in the sinus rate, but ST at rest without physiological triggers may also represent a spectrum of normal. In other cases, ST may not have an easily explainable cause but may represent serious underlying pathology and can be associated with intolerable symptoms. The classification of ST, consideration of possible etiologies, as well as the decisions of when and how to intervene can be difficult. ST can be classified as secondary to a specific, usually treatable, medical condition (eg, pulmonary embolism, anemia, infection, or hyperthyroidism) or be related to several incompletely defined conditions (eg, inappropriate ST, postural tachycardia syndrome, mast cell disorder, or post-COVID syndrome). While cardiologists and cardiac electrophysiologists often evaluate patients with symptoms associated with persistent or paroxysmal ST, an optimal approach remains uncertain. Due to the many possible conditions associated with ST, and an overlap in medical specialists who see these patients, the inclusion of experts in different fields is essential for a more comprehensive understanding. This article is unique in that it was composed by international experts in Neurology, Psychology, Autonomic Medicine, Allergy and Immunology, Exercise Physiology, Pulmonology and Critical Care Medicine, Endocrinology, Cardiology, and Cardiac Electrophysiology in the hope that it will facilitate a more complete understanding and thereby result in the better care of patients with ST.
MeSH term(s)	COVID-19 ; Humans ; Postural Orthostatic Tachycardia Syndrome ; Tachycardia, Sinus/diagnosis ; Tachycardia, Sinus/therapy
Language	English
Publishing date	2022-09-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2426129-4
ISSN	1941-3084 ; 1941-3149
ISSN (online)	1941-3084
ISSN	1941-3149
DOI	10.1161/CIRCEP.121.007960
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Zs.A 6667: Show issues

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Article ; Online: Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

Raj, Satish R / Bourne, Kate M / Stiles, Lauren E / Miglis, Mitchell G / Cortez, Melissa M / Miller, Amanda J / Freeman, Roy / Biaggioni, Italo / Rowe, Peter C / Sheldon, Robert S / Shibao, Cyndya A / Diedrich, Andre / Systrom, David M / Cook, Glen A / Doherty, Taylor A / Abdallah, Hasan I / Grubb, Blair P / Fedorowski, Artur / Stewart, Julian M /

Arnold, Amy C / Pace, Laura A / Axelsson, Jonas / Boris, Jeffrey R / Moak, Jeffrey P / Goodman, Brent P / Chémali, Kamal R / Chung, Tae H / Goldstein, David S / Darbari, Anil / Vernino, Steven

Autonomic neuroscience : basic & clinical

2021 Volume 235, Page(s) 102836

Abstract: The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to ... ...

Abstract	The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.
MeSH term(s)	Autonomic Nervous System ; Consensus ; Humans ; National Institutes of Health (U.S.) ; Orthostatic Intolerance ; Postural Orthostatic Tachycardia Syndrome/diagnosis ; Postural Orthostatic Tachycardia Syndrome/therapy ; United States
Language	English
Publishing date	2021-06-30
Publishing country	Netherlands
Document type	Consensus Development Conference, NIH ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2020105-9
ISSN	1872-7484 ; 1566-0702
ISSN (online)	1872-7484
ISSN	1566-0702
DOI	10.1016/j.autneu.2021.102836
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Zs.A 1533: Show issues

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Article ; Online: Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Vernino, Steven / Bourne, Kate M / Stiles, Lauren E / Grubb, Blair P / Fedorowski, Artur / Stewart, Julian M / Arnold, Amy C / Pace, Laura A / Axelsson, Jonas / Boris, Jeffrey R / Moak, Jeffrey P / Goodman, Brent P / Chémali, Kamal R / Chung, Tae H / Goldstein, David S / Diedrich, Andre / Miglis, Mitchell G / Cortez, Melissa M / Miller, Amanda J /

Freeman, Roy / Biaggioni, Italo / Rowe, Peter C / Sheldon, Robert S / Shibao, Cyndya A / Systrom, David M / Cook, Glen A / Doherty, Taylor A / Abdallah, Hasan I / Darbari, Anil / Raj, Satish R

Autonomic neuroscience : basic & clinical

2021 Volume 235, Page(s) 102828

Abstract: Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation ... ...

Abstract	Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.
MeSH term(s)	Adolescent ; Consensus ; Female ; Heart Rate ; Humans ; National Institutes of Health (U.S.) ; Orthostatic Intolerance ; Postural Orthostatic Tachycardia Syndrome/diagnosis ; Postural Orthostatic Tachycardia Syndrome/therapy ; United States
Language	English
Publishing date	2021-06-05
Publishing country	Netherlands
Document type	Consensus Development Conference, NIH ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2020105-9
ISSN	1872-7484 ; 1566-0702
ISSN (online)	1872-7484
ISSN	1566-0702
DOI	10.1016/j.autneu.2021.102828
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Zs.A 1533: Show issues

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Article ; Online: Structural Valve Deterioration After Self-Expanding Transcatheter or Surgical Aortic Valve Implantation in Patients at Intermediate or High Risk.

O'Hair, Daniel / Yakubov, Steven J / Grubb, Kendra J / Oh, Jae K / Ito, Saki / Deeb, G Michael / Van Mieghem, Nicolas M / Adams, David H / Bajwa, Tanvir / Kleiman, Neal S / Chetcuti, Stanley / Søndergaard, Lars / Gada, Hemal / Mumtaz, Mubashir / Heiser, John / Merhi, William M / Petrossian, George / Robinson, Newell / Tang, Gilbert H L /

Rovin, Joshua D / Little, Stephen H / Jain, Renuka / Verdoliva, Sarah / Hanson, Tim / Li, Shuzhen / Popma, Jeffrey J / Reardon, Michael J

JAMA cardiology

2022 Volume 8, Issue 2, Page(s) 111–119

Abstract: Importance: The frequency and clinical importance of structural valve deterioration (SVD) in patients undergoing self-expanding transcatheter aortic valve implantation (TAVI) or surgery is poorly understood.: Objective: To evaluate the 5-year ... ...

Abstract	Importance: The frequency and clinical importance of structural valve deterioration (SVD) in patients undergoing self-expanding transcatheter aortic valve implantation (TAVI) or surgery is poorly understood. Objective: To evaluate the 5-year incidence, clinical outcomes, and predictors of hemodynamic SVD in patients undergoing self-expanding TAVI or surgery. Design, setting, and participants: This post hoc analysis pooled data from the CoreValve US High Risk Pivotal (n = 615) and SURTAVI (n = 1484) randomized clinical trials (RCTs); it was supplemented by the CoreValve Extreme Risk Pivotal trial (n = 485) and CoreValve Continued Access Study (n = 2178). Patients with severe aortic valve stenosis deemed to be at intermediate or increased risk of 30-day surgical mortality were included. Data were collected from December 2010 to June 2016, and data were analyzed from December 2021 to October 2022. Interventions: Patients were randomized to self-expanding TAVI or surgery in the RCTs or underwent self-expanding TAVI for clinical indications in the nonrandomized studies. Main outcomes and measures: The primary end point was the incidence of SVD through 5 years (from the RCTs). Factors associated with SVD and its association with clinical outcomes were evaluated for the pooled RCT and non-RCT population. SVD was defined as (1) an increase in mean gradient of 10 mm Hg or greater from discharge or at 30 days to last echocardiography with a final mean gradient of 20 mm Hg or greater or (2) new-onset moderate or severe intraprosthetic aortic regurgitation or an increase of 1 grade or more. Results: Of 4762 included patients, 2605 (54.7%) were male, and the mean (SD) age was 82.1 (7.4) years. A total of 2099 RCT patients, including 1128 who received TAVI and 971 who received surgery, and 2663 non-RCT patients who received TAVI were included. The cumulative incidence of SVD treating death as a competing risk was lower in patients undergoing TAVI than surgery (TAVI, 2.20%; surgery, 4.38%; hazard ratio [HR], 0.46; 95% CI, 0.27-0.78; P = .004). This lower risk was most pronounced in patients with smaller annuli (23 mm diameter or smaller; TAVI, 1.32%; surgery, 5.84%; HR, 0.21; 95% CI, 0.06-0.73; P = .02). SVD was associated with increased 5-year all-cause mortality (HR, 2.03; 95% CI, 1.46-2.82; P < .001), cardiovascular mortality (HR, 1.86; 95% CI, 1.20-2.90; P = .006), and valve disease or worsening heart failure hospitalizations (HR, 2.17; 95% CI, 1.23-3.84; P = .008). Predictors of SVD were developed from multivariate analysis. Conclusions and relevance: This study found a lower rate of SVD in patients undergoing self-expanding TAVI vs surgery at 5 years. Doppler echocardiography was a valuable tool to detect SVD, which was associated with worse clinical outcomes. Trial registration: ClinicalTrials.gov Identifiers: NCT01240902, NCT01586910, and NCT01531374.
MeSH term(s)	Male ; Humans ; Aged, 80 and over ; Female ; Aortic Valve/surgery ; Treatment Outcome ; Transcatheter Aortic Valve Replacement/adverse effects ; Aortic Valve Stenosis ; Heart Valve Prosthesis Implantation
Language	English
Publishing date	2022-12-01
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2380-6591
ISSN (online)	2380-6591
DOI	10.1001/jamacardio.2022.4627
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Article ; Online: New strategies for enzyme replacement therapy for lysosomal storage diseases.

Grubb, Jeffrey H / Vogler, Carole / Sly, William S

Rejuvenation research

2010 Volume 13, Issue 2-3, Page(s) 229–236

Abstract: Enzyme replacement therapy is an established means of treating lysosomal storage diseases. Infused enzymes are normally targeted to the lysosomes of affected cells by interactions with cell-surface receptors that recognize carbohydrate moieties such as ... ...

Abstract	Enzyme replacement therapy is an established means of treating lysosomal storage diseases. Infused enzymes are normally targeted to the lysosomes of affected cells by interactions with cell-surface receptors that recognize carbohydrate moieties such as mannose and mannose 6-phosphate on the enzymes. Therefore, we have investigated alternative strategies to deliver the lysosomal enzyme beta-glucuronidase in the enzyme-deficient mucopolysaccharidosis type VII mouse model. Here we summarize our recent efforts to use nontraditional ways to deliver beta-glucuronidase. First, we used a chimeric protein of the insulin-like growth factor II (IGF-II) fused to beta-glucuronidase to deliver enzyme via the IGF-II binding site on the bifunctional IGF-II/mannose 6-phosphate receptor. Second, we used the 11-amino-acid human immunodeficiency virus (HIV) Tat domain fused to beta-glucuronidase to mediate uptake by absorptive endocytosis. Interaction with heparan sulfate on the cell surface internalizes and delivers the Tat-tagged enzyme to the lysosome via plasma membrane recycling. Third, we created a chimeric beta-glucuronidase fused to the Fc portion of human immunoglobulin G (IgG) Fc, which was transported by the neonatal Fc receptor from the maternal circulation across the placenta to sites of storage in fetal tissues. Finally, periodate treatment was used to eliminate interaction with carbohydrate receptors, creating an enzyme with increased plasma half-life, resulting in transport across the blood-brain barrier and clearance of storage in neurons. These strategies for delivering lysosomal enzymes could also be used to target nonlysosomal proteins or enzymes identified for bioremediation of other conditions.
MeSH term(s)	Animals ; Drug Delivery Systems/methods ; Enzyme Replacement Therapy/methods ; Enzyme Replacement Therapy/trends ; Glucuronidase/administration & dosage ; Glucuronidase/genetics ; Glucuronidase/pharmacokinetics ; Glucuronidase/therapeutic use ; Glycosylation ; Humans ; Lysosomal Storage Diseases/drug therapy ; Lysosomes/metabolism ; Mice ; Protein Sorting Signals/genetics ; Protein Transport ; Recombinant Fusion Proteins/administration & dosage ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/pharmacokinetics ; Recombinant Fusion Proteins/therapeutic use
Chemical Substances	Protein Sorting Signals ; Recombinant Fusion Proteins ; Glucuronidase (EC 3.2.1.31)
Language	English
Publishing date	2010-09-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2150779-X
ISSN	1557-8577 ; 1549-1684
ISSN (online)	1557-8577
ISSN	1549-1684
DOI	10.1089/rej.2009.0920
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Zs.A 5215: Show issues

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Article ; Online: Biochemical evidence for superior correction of neuronal storage by chemically modified enzyme in murine mucopolysaccharidosis VII.

Huynh, Ha T / Grubb, Jeffrey H / Vogler, Carole / Sly, William S

Proceedings of the National Academy of Sciences of the United States of America

2012 Volume 109, Issue 42, Page(s) 17022–17027

Abstract: Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the blood-brain barrier (BBB). We recently reported that PerT-GUS, ...

Abstract	Enzyme replacement therapy has been used successfully in many lysosomal storage diseases. However, correction of brain storage has been limited by the inability of infused enzyme to cross the blood-brain barrier (BBB). We recently reported that PerT-GUS, a form of β-glucuronidase (GUS) chemically modified to eliminate its uptake and clearance by carbohydrate-dependent receptors, crossed the BBB and cleared neuronal storage in an immunotolerant model of murine mucopolysaccharidosis (MPS) type VII. In this respect, the chemically modified enzyme was superior to native β-glucuronidase. Chemically modified enzyme was also delivered more effectively to heart, kidney, and muscle. However, liver and spleen, which express high levels of carbohydrate receptors, received nearly fourfold lower levels of PerT-GUS compared with native GUS. A recent report on PerT-treated sulfamidase in murine MPS IIIA confirmed enhanced delivery to other tissues but failed to observe clearance of storage in neurons. To confirm and extend our original observations, we compared the efficacy of 12 weekly i.v. infusions of PerT-GUS versus native GUS on (i) delivery of enzyme to brain; (ii) improvement in histopathology; and (iii) correction of secondary elevations of other lysosomal enzymes. Such correction is a recognized biomarker for correction of neuronal storage. PerT-GUS was superior to native GUS in all three categories. These results provide additional evidence that long-circulating enzyme, chemically modified to escape carbohydrate-mediated clearance, may offer advantages in treating MPS VII. The relevance of this approach to treat other lysosomal storage diseases that affect brain awaits confirmation.
MeSH term(s)	Animals ; Blood-Brain Barrier/metabolism ; Dose-Response Relationship, Drug ; Enzyme Replacement Therapy/methods ; Glucuronidase/genetics ; Glucuronidase/metabolism ; Glucuronidase/therapeutic use ; Glycosaminoglycans/metabolism ; Mice ; Mucopolysaccharidosis VII/drug therapy ; Mucopolysaccharidosis VII/enzymology ; Neurons/drug effects ; beta-Glucosidase/genetics ; beta-Glucosidase/metabolism ; beta-Glucosidase/therapeutic use
Chemical Substances	Glycosaminoglycans ; beta-Glucosidase (EC 3.2.1.21) ; Glucuronidase (EC 3.2.1.31) ; PerT-GUS (EC 3.2.1.31)
Language	English
Publishing date	2012-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1214779109
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Genomic data analysis workflows for tumors from patient-derived xenografts (PDXs): challenges and guidelines.

Woo, Xing Yi / Srivastava, Anuj / Graber, Joel H / Yadav, Vinod / Sarsani, Vishal Kumar / Simons, Al / Beane, Glen / Grubb, Stephen / Ananda, Guruprasad / Liu, Rangjiao / Stafford, Grace / Chuang, Jeffrey H / Airhart, Susan D / Karuturi, R Krishna Murthy / George, Joshy / Bult, Carol J

BMC medical genomics

2019 Volume 12, Issue 1, Page(s) 92

Abstract: Background: Patient-derived xenograft (PDX) models are in vivo models of human cancer that have been used for translational cancer research and therapy selection for individual patients. The Jackson Laboratory (JAX) PDX resource comprises 455 models ... ...

Abstract	Background: Patient-derived xenograft (PDX) models are in vivo models of human cancer that have been used for translational cancer research and therapy selection for individual patients. The Jackson Laboratory (JAX) PDX resource comprises 455 models originating from 34 different primary sites (as of 05/08/2019). The models undergo rigorous quality control and are genomically characterized to identify somatic mutations, copy number alterations, and transcriptional profiles. Bioinformatics workflows for analyzing genomic data obtained from human tumors engrafted in a mouse host (i.e., Patient-Derived Xenografts; PDXs) must address challenges such as discriminating between mouse and human sequence reads and accurately identifying somatic mutations and copy number alterations when paired non-tumor DNA from the patient is not available for comparison. Results: We report here data analysis workflows and guidelines that address these challenges and achieve reliable identification of somatic mutations, copy number alterations, and transcriptomic profiles of tumors from PDX models that lack genomic data from paired non-tumor tissue for comparison. Our workflows incorporate commonly used software and public databases but are tailored to address the specific challenges of PDX genomics data analysis through parameter tuning and customized data filters and result in improved accuracy for the detection of somatic alterations in PDX models. We also report a gene expression-based classifier that can identify EBV-transformed tumors. We validated our analytical approaches using data simulations and demonstrated the overall concordance of the genomic properties of xenograft tumors with data from primary human tumors in The Cancer Genome Atlas (TCGA). Conclusions: The analysis workflows that we have developed to accurately predict somatic profiles of tumors from PDX models that lack normal tissue for comparison enable the identification of the key oncogenic genomic and expression signatures to support model selection and/or biomarker development in therapeutic studies. A reference implementation of our analysis recommendations is available at https://github.com/TheJacksonLaboratory/PDX-Analysis-Workflows .
MeSH term(s)	Animals ; Cell Transformation, Neoplastic ; DNA Copy Number Variations ; Gene Expression Profiling ; Genomics/methods ; Humans ; Lymphoma/genetics ; Lymphoma/pathology ; Mice ; Neoplasms/genetics ; Neoplasms/pathology ; Point Mutation ; Polymorphism, Single Nucleotide ; Workflow
Language	English
Publishing date	2019-07-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2411865-5
ISSN	1755-8794 ; 1755-8794
ISSN (online)	1755-8794
ISSN	1755-8794
DOI	10.1186/s12920-019-0551-2
Database	MEDical Literature Analysis and Retrieval System OnLINE

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