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Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone 下载免费PDF全文
Stewart VA McGrath SM Dubois PM Pau MG Mettens P Shott J Cobb M Burge JR Larson D Ware LA Demoitie MA Weverling GJ Bayat B Custers JH Dubois MC Cohen J Goudsmit J Heppner DG 《Infection and immunity》2007,75(5):2283-2290
The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans. 相似文献
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Bloch-Queyrat C Fondanèche MC Chen R Yin L Relouzat F Veillette A Fischer A Latour S 《The Journal of experimental medicine》2005,202(1):181-192
SAP is an adaptor protein that is expressed in NK and T cells. It is mutated in humans who have X-linked lymphoproliferative (XLP) disease. By interacting with SLAM family receptors, SAP enables tyrosine phosphorylation signaling of these receptors by its ability to recruit the Src-related kinase, Fyn. Here, we analyzed the role of SAP in NK cell functions using the SAP-deficient mouse model. Our results showed that SAP was required for the ability of NK cells to eliminate tumor cells in vitro and in vivo. This effect strongly correlated with expression of CD48 on tumor cells, the ligand of 2B4, a SLAM-related receptor expressed in NK cells. In keeping with earlier reports that studied human NK cells, we showed that SAP was necessary for the ability of 2B4 to trigger cytotoxicity and IFN-gamma secretion. In the absence of SAP, 2B4 function was shifted toward inhibition of NK cell-mediated cytotoxicity. By analyzing mice lacking Fyn, we showed that similarly to SAP, Fyn was strictly required for 2B4 function. Taken together, these results provide evidence that the 2B4-SAP-Fyn cascade defines a potent activating pathway of natural cytotoxicity. They also could help to explain the high propensity of patients who have XLP disease to develop lymphoproliferative disorders. 相似文献
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OBJECTIVE: To examine the influence of life course socioeconomic disadvantages (SED) on cognitive function in later life. METHOD: Data originate from a survey of people 60 and older living in seven Latin American and Caribbean cities. Cognitive function was measured with a modified Mini-Mental State Examination and the Pfeffer Scale of Functional Capacity. Homogeneity tests were used to pool data. Associations between cognitive function and SED were evaluated, fitting logistic regressions. RESULTS: Cognitive impairment (CI) prevalence ranged from 0.3% to 6.5% in men and 1.2% to 10.1% in women. Childhood rural living, poor childhood health, illiteracy, housewife or farmer occupation, and insufficient income were associated with CI in all seven cities. The odds of CI increase with cumulative exposure to disadvantages along life course. CONCLUSIONS: Life course SED is related to cognitive function later in life. Difficulty in properly distinguishing cognitive function from test performance remains an issue. 相似文献
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A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. 总被引:11,自引:0,他引:11
Christophe Loubeyre Marie-Claude Morice Thierry Lefèvre Jean-Fran?ois Piéchaud Yves Louvard Pierre Dumas 《Journal of the American College of Cardiology》2002,39(1):15-21
OBJECTIVES: We sought to determine whether direct stenting might prevent the adverse events associated with stent implantation during primary angioplasty and to compare it with conventional stent implantation in patients with acute myocardial infarction (AMI). BACKGROUND: No trial has demonstrated that stents favorably influence mortality rate. Recent studies have even suggested a negative impact of stents on coronary blood flow and clinical outcome. METHODS: Of 409 patients treated by primary angioplasty with stent implantation in our center, 206 (50%) were enrolled in this randomized, single-center trial and allocated to direct stent implantation (n = 102) or stent implantation after balloon pre-dilation (n = 104). The study end points included angiographic results (final corrected Thrombolysis In Myocardial Infarction [TIMI] frame count and a composite end point of slow and no-reflow or distal embolization), an electrocardiogram marker of myocardial reperfusion assessment (ST-segment resolution) and in-hospital clinical outcome (death and recurrent infarction). RESULTS: Direct stent implantation failed in eight patients but succeeded after pre-dilation in all. A non-significant increase in TIMI flow grade 3 was achieved after direct stenting (95.1% vs. 93.3%, p = 0.74) without significant difference in the corrected TIMI frame count (31.5 +/- 17 and 35.2 +/- 20 frames after direct and conventional stent, respectively, p = 0.42). The composite angiographic end point was significantly reduced by direct stent implantation (11.7% vs. 26.9%, p = 0.01). ST-segment resolution was also significantly improved after direct stent (no ST-segment resolution in 20.2% vs. 38.1% after direct and conventional stent, respectively, p = 0.01). Death and/or recurrent infarction occurred in six patients after conventional stent implantation and in two patients after direct stenting (p = 0.28). CONCLUSIONS: In selected patients with AMI, direct stenting can be applied safely and effectively. This strategy may result in a significant reduction of microvascular injury, as suggested by improved ST-segment resolution after reperfusion with major potential clinical consequences. 相似文献
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Lydie Boussicault Anne-Sophie Hérard Noel Calingasan Fanny Petit Carole Malgorn Nicolas Merienne Caroline Jan Marie-Claude Gaillard Rodrigo Lerchundi Luis F Barros Carole Escartin Thierry Delzescaux Jean Mariani Philippe Hantraye M Flint Beal Emmanuel Brouillet Céline Véga Gilles Bonvento 《Journal of cerebral blood flow and metabolism》2014,34(9):1500-1510
Huntington''s disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD. 相似文献
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Patricia Facchinetti Emilie Dorard Vincent Contremoulins Marie-Claude Gaillard Nicole Déglon Véronique Sazdovitch Chantal Guihenneuc-Jouyaux Emmanuel Brouillet Charles Duyckaerts Bernadette Allinquant 《Neurobiology of aging》2014
Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation. 相似文献