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51.
Mario Gimona Maria Felice Brizzi Andre Boon Hwa Choo Massimo Dominici Sean M. Davidson Johannes Grillari Dirk M. Hermann Andrew F. Hill Dominique de Kleijn Ruenn Chai Lai Charles P. Lai Rebecca Lim Marta Monguió-Tortajada Maurizio Muraca Takahiro Ochiya Luis A. Ortiz Wei Seong Toh Yong Weon Yi Sai Kiang Lim 《Cytotherapy》2021,23(5):373-380
Mesenchymal stromal/stem cells (MSCs) have been widely tested against many diseases, with more than 1000 registered clinical trials worldwide. Despite many setbacks, MSCs have been approved for the treatment of graft-versus-host disease and Crohn disease. However, it is increasingly clear that MSCs exert their therapeutic functions in a paracrine manner through the secretion of small extracellular vesicles (sEVs) of 50–200 nm in diameter. Unlike living cells that can persist long-term, sEVs are non-living and non-replicative and have a transient presence in the body. Their small size also renders sEV preparations highly amenable to sterilization by filtration. Together, acellular MSC-sEV preparations are potentially safer and easier to translate into the clinic than cellular MSC products. Nevertheless, there are inherent challenges in the development of MSC-sEV drug products. MSC-sEVs are products of living cells, and living cells are sensitive to changes in the external microenvironment. Consequently, quality control metrics to measure key identity and potency features of MSC-sEV preparations have to be specified during development of MSC-sEV therapeutics. The authors have previously described quantifiable assays to define the identity of MSC-sEVs. Here the authors discuss requirements for prospective potency assays to predict the therapeutic effectiveness of the drug substance in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines. Although potency assays should ideally reflect the mechanism of action (MoA), this is challenging because the MoA for the reported efficacy of MSC-sEV preparations against multiple diseases of diverse underlying pathology is likely to be complex and different for each disease and difficult to fully elucidate. Nevertheless, robust potency assays could be developed by identifying the EV attribute most relevant to the intended biological activity in EV-mediated therapy and quantifying the EV attribute. Specifically, the authors highlight challenges and mitigation measures to enhance the manufacture of consistent and reproducibly potent sEV preparations, to identify and select the appropriate EV attribute for potency assays despite a complex “work-in-progress” MoA and to develop assays likely to be compliant with regulatory guidance for assay validation. 相似文献
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Andre Vosloo Anél Laas Dalene Vosloo 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2013,164(1):192-199
Marine invertebrates have evolved multiple responses to naturally variable environmental oxygen, all aimed at either maintaining cellular oxygen homeostasis or limiting cellular damage during or after hypoxic or hyperoxic events. We assessed organismal (rates of oxygen consumption and ammonia excretion) and cellular (heat shock protein expression, anti-oxidant enzymes) responses of juvenile and adult abalone exposed to low (~ 83% of saturation), intermediate (~ 95% of saturation) and high (~ 115% of saturation) oxygen levels for one month. Using the Comet assay, we measured DNA damage to determine whether the observed trends in the protective responses were sufficient to prevent oxidative damage to cells. Juveniles were unaffected by moderately hypoxic and hyperoxic conditions. Elevated basal rates of superoxide dismutase, glutathione peroxidase and catalase were sufficient to prevent DNA fragmentation and protein damage. Adults, with their lower basal rate of anti-oxidant enzymes, had increased DNA damage under hypoxic and hyperoxic conditions, indicating that the antioxidant enzymes were unable to prevent oxidative damage under hypoxic and hyperoxic conditions. The apparent insensitivity of juvenile abalone to decreased and increased oxygen might be related to their life history and development in algal and diatom biofilms where they are exposed to extreme diurnal fluctuations in dissolved oxygen levels. 相似文献
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Jagar?JasemEmail author Kawa?Marof Adnan?Nawar Yosra?Khalaf Sirwan?Aswad Faisal?Hamdani Monirul?Islam Andre?Kalil 《BMC neurology》2013,13(1):195
Background
Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis (AFP) in the post-poliomyelitis eradication era. This is the first study done to identify the epidemiology, clinical features, and outcome of GBS in Iraqi children over 15 years.Methods
The surveillance database about AFP cases?<?15 years reported during January 1997-December 2011 was used.Results
GBS represented 52.5% of AFP cases, with an incidence of 1.33 case/100,000 population?<?15 years/year. There was a higher incidence in the Southern provinces, age group 1–4 years, males, and outside the capital city of province, with no significant seasonal variations (p?=?.22). Survival probability after the 1 year of onset for those with respiratory muscle involvement was .76 (95% CI: .60-.86), versus .97 (95% Cl: .96-.98) for those who did not develop it (p?<?.001); and .97 (95% CI: .96-.98) for those living inside the capital city, versus .94 (.93-.95) for those living outside (p?=?.001). Cumulative incidence of residual paralysis for patients living inside the capital city was .21 (95% CI: .18-.24), versus .27 (95% CI: .25-.29) for those living outside (p?<?.001).Conclusions
The incidence, age and gender distribution, and seasonality of GBS among Iraqi children is similar to those reported from other previous studies. It is the most important cause of AFP, especially in those between the age of 1 to 4 years living in rural areas.56.
Abstract The 5′-O-(4,4′-dimethoxytrityl) and 5′-O-(tert-butyldimethylsilyl) derivatives of 2′-,3′-O-thiocarbonyl-6-azauridine and 2′,3′-O-thiocarbonyl-5-chlorouridine were synthesized from the parent nucleosides by reaction with 4, 4′-dimethoxytrityl chloride and tert-butyldimethylsilyl chloride, respectively, followed by treatment with 1,1′-thiocarbonyldiimidazole. Introduction of a 2′-,3′-double bond into the sugar ring by reaction of the 5′-protected 2′-,3′-O-thionocarbonates with 1, 3-dimethyl-2-phenyl-1, 3, 2-diazaphospholidiine was unsuccessful, but could be accomplished satisfactorily with trimethyl phosphite. Reactions were generally more successful with the 5′-silylated than with the 5′-tritylated nucleosides. Formation of 2′-,3′-O-thiocarbonyl derivatives proceeded in higher yield with 5′-protected 6-azauridines than with the corresponding 5-chlorouridines because of the propensity of the latter to form 2,2′-anhydro derivatives. In the reaction of 5′-O-(tert-butyldimethylsilyl)-2′-,3′-O-thiocarbonyl-6-azauridine with trimethyl phosphite, introduction of the double bond was accompanied by N3-methylation. However this side reaction was not a problem with 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-O-thioarbonyl-5-chlorouridine. Treatment of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-6-azauridine with tetrabutylammonium fluoride followed by hydrogenation afforded 2′-,3′-dideoxy-6-azauridine. Deprotection of 5′-O-(tert-butyldimethylsilyl)-2′-, 3′-didehydro-2′-,3′-dideoxy-5-chlorouridine yielded 2′-,3′-didehydro-2′-,3′-dide-oxy-5-chlorouridine. 相似文献
57.
Jayanta Saha Ruth M. Ruprecht Andre Rosowsky 《Nucleosides, nucleotides & nucleic acids》2013,32(7):1465-1475
Abstract A convenient general method of synthesis of 5′-O-(alkoxycarbonyl)phosphonate esters of 2′,3′-dideoxyribonucleosides is presented, using the 5′-O-(methoxycarbonyl)phosphinyl, 5′-0-(ethoxycarbonyl)phosphinyl, and 5′-O-(cholesterylcarbonyl)phosphinyl derivatives of 3′-azido-3′-deoxythymidine (AZT) and the 5′-0-(ethoxycarbonyl)phosphinyl derivative of 2′,3′-dideoxycytidine (ddC) as examples. Reaction of trimethyl phosphonoformate, methyl phosphonoformate, or dimethyl cholesterylcarbonylphosphonate with phosphorus pentachloride in carbon tetrachloride, followed by direct condensation of the resulting phosphonyl chloride with the nucleoside, gave the fully esterified phosphonoformate derivatives, which on treatment with sodium iodide in tetrahydrofuran underwent selective cleavage of the P-OMe or P-OEt groups, leaving the carboxylate esters intact. The resulting products were converted from sodium salts to ammonium salts by ion-exchange chromatography. 相似文献
58.
Gilles Gosselin Christophe Mathé Marie-Christine Bergogne Anne-Marie Aubertin Andre Kirn Jean-Pierre Sommadossi 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):611-617
Abstract Several L-enantiomers of nucleoside analogues were stereospecifically synthesized by a multi-step reaction from L-xylose and their antiviral properties were examined in vitro. Two of them, namely β-L-2′,3,′-dideoxycytidine (β-L-ddC) and its 5-fluoro derivative (β-L-FddC) were found to have potent anti-human immunodeficiency virus (HIV) and significant anti-hepatitis B virus (HBV) activities in cell cultures. 相似文献
59.
The SER Primer on Ecological Restoration provides a succinct introduction to, and overview of, the rapidly growing field of ecological restoration. The Primer was issued initially in 2002 by the Society for Ecological Restoration (SER) and reissued verbatim 2 years later in a more attractive format ( http://www.ser.org/resources;resources-detail-view/ser-international-primer-on-ecological-restoration ). A SER committee recently began deliberations to update the Primer, and much discussion is underway. As two of the Primer's principal authors, we were invited to share our views on how the Primer can be advantageously revised in the light of any changes or new insights since 2002. In particular, we were asked how the Primer might be modified to reflect the ways that ecological restoration address conservation issues raised by climate change and other rapid environmental shifts and global changes. We also touch on questions relating to the benefits of ecological restoration to human society, as this is an area where the Primer needs sharper focus. We have structured the following in a ‘Frequently Asked Questions’ format to highlight issues raised in the recent literature and to focus attention on other issues that merit consideration in the Primer revision process. 相似文献
60.
Dave Kelly Andre Geldenhuis Alex James E. Penelope Holland Michael J. Plank Robert E. Brockie Philip E. Cowan Grant A. Harper William G. Lee Matt J. Maitland Alan F. Mark James A. Mills Peter R. Wilson Andrea E. Byrom 《Ecology letters》2013,16(1):90-98
Mast‐seeding plants often produce high seed crops the year after a warm spring or summer, but the warm‐temperature model has inconsistent predictive ability. Here, we show for 26 long‐term data sets from five plant families that the temperature difference between the two previous summers (ΔT) better predicts seed crops. This discovery explains how masting species tailor their flowering patterns to sites across altitudinal temperature gradients; predicts that masting will be unaffected by increasing mean temperatures under climate change; improves prediction of impacts on seed consumers; demonstrates that strongly masting species are hypersensitive to climate; explains the rarity of consecutive high‐seed years without invoking resource constraints; and generates hypotheses about physiological mechanisms in plants and insect seed predators. For plants, ΔT has many attributes of an ideal cue. This temperature‐difference model clarifies our understanding of mast seeding under environmental change, and could also be applied to other cues, such as rainfall. 相似文献