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41.
Einar Osland Vik-Mo Marta Nyakas Birthe Viftrup Mikkelsen Morten Carstens Moe Paulina Due-Tønnesen Else Marit Inderberg Suso Stein Sæbøe-Larssen Cecilie Sandberg Jan E. Brinchmann Eirik Helseth Anne-Marie Rasmussen Knut Lote Steinar Aamdal Gustav Gaudernack Gunnar Kvalheim Iver A. Langmoen 《Cancer immunology, immunotherapy : CII》2013,62(9):1499-1509
Background
The growth and recurrence of several cancers appear to be driven by a population of cancer stem cells (CSCs). Glioblastoma, the most common primary brain tumor, is invariably fatal, with a median survival of approximately 1 year. Although experimental data have suggested the importance of CSCs, few data exist regarding the potential relevance and importance of these cells in a clinical setting.Methods
We here present the first seven patients treated with a dendritic cell (DC)-based vaccine targeting CSCs in a solid tumor. Brain tumor biopsies were dissociated into single-cell suspensions, and autologous CSCs were expanded in vitro as tumorspheres. From these, CSC-mRNA was amplified and transfected into monocyte-derived autologous DCs. The DCs were aliquoted to 9–18 vaccines containing 107 cells each. These vaccines were injected intradermally at specified intervals after the patients had received a standard 6-week course of post-operative radio-chemotherapy. The study was registered with the ClinicalTrials.gov identifier NCT00846456.Results
Autologous CSC cultures were established from ten out of eleven tumors. High-quality RNA was isolated, and mRNA was amplified in all cases. Seven patients were able to be weaned from corticosteroids to receive DC immunotherapy. An immune response induced by vaccination was identified in all seven patients. No patients developed adverse autoimmune events or other side effects. Compared to matched controls, progression-free survival was 2.9 times longer in vaccinated patients (median 694 vs. 236 days, p = 0.0018, log-rank test).Conclusion
These findings suggest that vaccination against glioblastoma stem cells is safe, well-tolerated, and may prolong progression-free survival. 相似文献42.
The titanosaur sauropod Bonatitan reigi is redescribed. The material collected, originally interpreted as pertaining to two different individuals, is reorganised in five individuals, and the original type specimen is separated into three different individuals. One of the braincases is designated as a new type specimen. Some materials are described by the first time (sacral ribs, distal caudal, chevrons, metacarpals, astragalus and metatarsals), others reinterpreted as different bones (‘ulna’ and ‘radius’). The diagnosis of B. reigi is emended, removing some of the original characters (longitudinal groove located on the suture between the parietals that continues posteriorly over the supraoccipital to the foramen magnum) and adding some new (small paired pits on the frontals and posterior ridge of the metacarpal IV). The phylogenetic analysis does not support B. reigi as a member of the Saltasaurinae, but rather as a basal member of a broad clade of sauropods that in turn is recovered as the sister group of the Saltasauridae. 相似文献
43.
Sabiha Abekhoukh Chris Planque Clémentine Ripoll Paulina Urbaniak Jean-Louis Paul Jean-Maurice Delabar Nathalie Janel 《Molecular neurobiology》2013,47(1):105-116
Hyperhomocysteinemia due to cystathionine beta synthase (CBS) deficiency is associated with diverse brain disease. Whereas the biological actions linking hyperhomocysteinemia to the cognitive dysfunction are not well understood, we tried to establish relationships between hyperhomocysteinemia and alterations of signaling pathways. In the brain of CBS-deficient mice, a murine model of hyperhomocysteinemia, we previously found an activation of extracellular signal-regulated kinase (ERK) pathway and an increase of Dyrk1A, a serine/threonine kinase involved in diverse functions ranging from development and growth to apoptosis. We then investigated the relationship between Dyrk1A and the signaling pathways initiated by receptor tyrosine kinases (RTK), the ERK and PI3K/Akt pathways. We found a significant increase of phospho-ERK, phospho-MEK, and phospho-Akt in the brain of CBS-deficient and Dyrk1a-overexpressing mice. This increase was abolished when CBS-deficient and Dyrk1A-transgenic mice were treated with harmine, an inhibitor of Dyrk1A kinase activity, which emphasizes the role of Dyrk1A activity on ERK and Akt activation. Sprouty 2 protein level, a negative feedback loop modulator that limits the intensity and duration of RTK activation, is decreased in the brain of CBS-deficient mice, but not in the brain of Dyrk1A transgenic mice. Furthermore, a reduced Dyrk1A and Grb2 binding on sprouty 2 and an increased interaction of Dyrk1A with Grb2 were found in the brain of Dyrk1A transgenic mice. The consequence of Dyrk1A overexpression on RTK activation seems to be a decreased interaction of sprouty 2/Grb2. These observations demonstrate ERK and Akt activation induced by Dyrk1A in the brain of hyperhomocysteinemic mice and open new perspectives to understand the basis of the cognitive defects in hyperhomocysteinemia. 相似文献
44.
Heavy metal-induced oxidative damage, defense reactions, and detoxification mechanisms in plants 总被引:7,自引:0,他引:7
Oksana Sytar Abhay Kumar Dariusz Latowski Paulina Kuczynska Kazimierz Strzałka M. N. V. Prasad 《Acta Physiologiae Plantarum》2013,35(4):985-999
Heavy metal (HMs) contamination is widespread globally due to anthropogenic, technogenic, and geogenic activities. The HMs exposure could lead to multiple toxic effects in plants by inducing reactive oxygen species (ROS), which inhibit most cellular processes at various levels of metabolism. ROS being highly unstable could play dual role (1) damaging cellular components and (2) act as an important secondary messenger for inducing plant defense system. Cells are equipped with enzymatic and non-enzymatic defense mechanisms to counteract this damage. Some are constitutive and others that are activated only when a stress-specific signal is perceived. Enzymatic scavengers of ROS include superoxide dismutase, catalase, glutathione reductase, and peroxidase, while non-enzymatic antioxidants are glutathione, ascorbic acid, α-tocopherol, flavonoids, anthocyanins, carotenoids, and organic acids. The intracellular and extracellular chelation mechanisms of HMs are associated with organic acids such as citric, malic and oxalic acid, etc. The important mechanism of detoxification includes metal complexation with glutathione, amino acids, synthesis of phytochelatins and sequestration into the vacuoles. Excessive stresses induce a cascade, MAPK (mitogen-activated protein kinase) pathway and synthesis of metal-detoxifying ligands. Metal detoxification through MAPK cascade and synthesis of metal-detoxifying ligands will be of considerable interest in the field of plant biotechnology. Further, the photoprotective roles of pigments of xanthophylls cycle under HMs stress were also discussed. 相似文献
45.
Ludovic D'Auria Marisa Fenaux Paulina Aleksandrowicz Patrick Van Der Smissen Christophe Chantrain Christiane Vermylen Miikka Vikkula Pierre J. Courtoy Donatienne Tyteca 《Journal of lipid research》2013,54(4):1066-1076
Micrometric membrane lipid segregation is controversial. We addressed this issue in attached erythrocytes and found that fluorescent boron dipyrromethene (BODIPY) analogs of glycosphingolipids (GSLs) [glucosylceramide (BODIPY-GlcCer) and monosialotetrahexosylganglioside (GM1BODIPY)], sphingomyelin (BODIPY-SM), and phosphatidylcholine (BODIPY-PC inserted into the plasma membrane spontaneously gathered into distinct submicrometric domains. GM1BODIPY domains colocalized with endogenous GM1 labeled by cholera toxin. All BODIPY-lipid domains disappeared upon erythrocyte stretching, indicating control by membrane tension. Minor cholesterol depletion suppressed BODIPY-SM and BODIPY-PC but preserved BODIPY-GlcCer domains. Each type of domain exchanged constituents but assumed fixed positions, suggesting self-clustering and anchorage to spectrin. Domains showed differential association with 4.1R versus ankyrin complexes upon antibody patching. BODIPY-lipid domains also responded differentially to uncoupling at 4.1R complexes [protein kinase C (PKC) activation] and ankyrin complexes (in spherocytosis, a membrane fragility disease). These data point to micrometric compartmentation of polar BODIPY-lipids modulated by membrane tension, cholesterol, and differential association to the two nonredundant membrane:spectrin anchorage complexes. Micrometric compartmentation might play a role in erythrocyte membrane deformability and fragility. 相似文献
46.
Nicolás Fuenzalida‐Uribe Rodrigo C. Meza Hernán A. Hoffmann Rodrigo Varas Jorge M. Campusano 《Journal of neurochemistry》2013,125(2):281-290
Biogenic amines (BAs) play a central role in the generation of complex behaviors in vertebrates and invertebrates, including the fly Drosophila melanogaster. The comparative advantages of Drosophila as a genetic model to study the contribution of BAs to behaviors stumble upon the difficulty to access the fly brain to ask relevant physiological questions. For instance, it is not known whether the activation of nicotinic acetylcholine receptors (nAChRs) induces the release of BAs in fly brain, a phenomenon associated to several behaviors in vertebrates. Here, we describe a new preparation to study the efflux of BAs in the adult fly brain by in vitro chronoamperometry. Using this preparation we show that nAChR agonists including nicotine induce a fast, transient, dose‐dependent efflux of endogenous BAs, an effect mediated by α‐bungarotoxin‐sensitive nAChRs. By using different genetic tools we demonstrate that the BA whose efflux is induced by nAChR activation is octopamine (Oct). Furthermore, we show that the impairment of a mechanically induced startle response after nicotine exposure is not observed in flies deficient in Oct transmission. Thus, our data show that the efflux of BAs in Drosophila brain is increased by nAChR activation as in vertebrates, and that then AChR‐induced Oct release could have implications in a nicotine‐induced behavioral response. 相似文献
47.
Marian L. Kruzel Jeffrey K. Actor Michał Zimecki Jasen Wise Paulina Płoszaj Shaper Mirza Mark Kruzel Shen-An Hwang Xueqing Ba Istvan Boldogh 《Journal of biotechnology》2013
Lactoferrin, an iron-binding protein found in high concentrations in mammalian exocrine secretions, is an important component of the host defense system. It is also a major protein of the secondary granules of neutrophils from which is released upon activation. Due to its potential clinical utility, recombinant human lactoferrin (rhLF) has been produced in various eukaryotic expression systems; however, none of these are fully compatible with humans. Most of the biopharmaceuticals approved by the FDA for use in humans are produced in mammalian expression systems. The Chinese hamster ovary cells (CHO) have become the system of choice for proteins that require post-translational modifications, such as glycoproteins. 相似文献
48.
Alcoholism has complex etiology and there is evidence for both genetic and environmental factors in its pathophysiology. Chronic, long-term alcohol abuse and alcohol dependence are associated with neuronal loss with the prefrontal cortex being particularly susceptible to neurotoxic damage. This brain region is involved in the development and persistence of alcohol addiction and neurotoxic damage is likely to exacerbate the reinforcing effects of alcohol and may hinder treatment. Understanding the mechanism of alcohol’s neurotoxic effects on the brain and the genetic risk factors associated with alcohol abuse are the focus of current research. Because of its well-established role in neurodegenerative and neuropsychological disorders, and its emerging role in the pathophysiology of addiction, here we review the genetic and epigenetic factors involved in regulating α-synuclein expression and its potential role in the pathophysiology of chronic alcohol abuse. Elucidation of the mechanisms of α-synuclein regulation may prove beneficial in understanding the role of this key synaptic protein in disease and its potential for therapeutic modulation in the treatment of substance use disorders as well as other neurodegenerative diseases. 相似文献
49.
Marta Spodzieja Monika Rafalik Aneta Szymańska Aleksandra S. Kołodziejczyk Paulina Czaplewska 《Journal of molecular recognition : JMR》2013,26(9):415-425
Secondary amyloid A (AA) amyloidosis is an important complication of some chronic inflammatory diseases, primarily rheumatoid arthritis (RA). It is a serious, potentially life‐threatening disorder caused by the deposition of AA fibrils, which are derived from the circulatory, acute‐phase‐reactant, serum amyloid A protein (SAA). Recently, a specific interaction between SAA and the ubiquitous inhibitor of cysteine proteases—human cystatin C (hCC)—has been proved. Using a combination of selective proteolytic excision and high‐resolution mass spectrometry, the binding sites in the SAA and hCC sequences were assessed as SAA(86–104) and hCC(96–102), respectively. Here, we report further details concerning the hCC–SAA interaction. With the use of affinity tests and florescent ELISA‐like assays, the amino acid residues crucial for the protein interaction were determined. It was shown that all amino acid residues in the SAA sequence, essential for the formation of the protein complex, are basic ones, which suggests an electrostatic interaction character. The idea is corroborated by the fact that the most important residues in the hCC sequence are Ser‐98 and Tyr‐102; these residues are able to form hydrogen bonds via their hydroxyl groups. The molecular details of hCC–SAA complex formation might be helpful for the design of new compounds modulating the biological role of both proteins. Copyright © 2013 John Wiley & Sons, Ltd. 相似文献
50.
Daniel?SchmitterEmail author Paulina?Wachowicz Daniel?SageEmail author Anastasia?Chasapi Ioannis?Xenarios Viesturs?Simanis Michael?Unser 《Cell division》2013,8(1):6