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[PMID]: 25256739
[Au] Autor:Mineharu Y; Kamran N; Lowenstein PR; Castro MG
[Ad] Address:Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, Michigan....
[Ti] Title:Blockade of mTOR Signaling via Rapamycin Combined with Immunotherapy Augments Antiglioma Cytotoxic and Memory T-Cell Functions.
[So] Source:Mol Cancer Ther;13(12):3024-36, 2014 Dec.
[Is] ISSN:1538-8514
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The success of immunotherapeutic approaches targeting glioblastoma multiforme (GBM) demands a robust antiglioma T-cell cytotoxic and memory response. Recent evidence suggests that rapamycin regulates T-cell differentiation. Herein, we tested whether administration of rapamycin could enhance the efficacy of immunotherapy utilizing Fms-like tyrosine kinase 3 ligand (Ad-Flt3L) and thymidine kinase/ganciclovir (Ad-TK/GCV). Using the refractory rat RG2 glioma model, we demonstrate that administration of rapamycin with Ad-Flt3L + Ad-TK/GCV immunotherapy enhanced the cytotoxic activity of antitumor CD8(+) T cells. Rats treated with rapamycin + Ad-Flt3L + Ad-TK/GCV exhibited massive reduction in the tumor volume and extended survival. Rapamycin administration also prolonged the survival of Ad-Flt3L + Ad-TK/GCV-treated GL26 tumor-bearing mice, associated with an increase in the frequency of tumor-specific and IFNγ(+) CD8(+) T cells. More importantly, rapamycin administration, even for a short interval, elicited a potent long-lasting central memory CD8(+) T-cell response. The enhanced memory response translated to an increased frequency of tumor-specific CD8(+) T cells within the tumor and IFNγ release, providing the mice with long-term survival advantage in response to tumor rechallenge. Our data, therefore, point to rapamycin as an attractive adjuvant to be used in combination with immunotherapy in a phase I clinical trial for GBM. Mol Cancer Ther; 13(12); 3024-36. ©2014 AACR.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1158/1535-7163.MCT-14-0400

  2 / 252801 MEDLINE  
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[PMID]: 25367116
[Au] Autor:Manes TD; Pober JS
[Ad] Address:Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 thomas.manes@yale.edu.
[Ti] Title:Polarized granzyme release is required for antigen-driven transendothelial migration of human effector memory CD4 T cells.
[So] Source:J Immunol;193(12):5809-15, 2014 Dec 15.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Human effector memory CD4 T cells may transmigrate across endothelial cell (EC) monolayers either in response to inflammatory chemokines or in response to TCR recognition of Ag presented on the surface of the EC. The kinetics, morphologic manifestations, and molecular requirements of chemokine- and TCR-driven transendothelial migration (TEM) differ significantly. In this study, we report that, whereas the microtubule organizing center (MTOC) and cytosolic granules follow the nucleus across the endothelium in a uropod during chemokine-driven TEM, MTOC reorientation to the contact region between the T cell and the EC, accompanied by dynein-driven transport of granzyme-containing granules to and exocytosis at the contact region, are early events in TCR-driven, but not chemokine-driven TEM. Inhibitors of either granule function or granzyme proteolytic activity can arrest TCR-driven TEM, implying a requirement for granule discharge in the process. In the final stages of TCR-driven TEM, the MTOC precedes, rather than follows, the nucleus across the endothelium. Thus, TCR-driven TEM of effector memory CD4 T cells appears to be a novel process that more closely resembles immune synapse formation than it does conventional chemotaxis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1401665

  3 / 252801 MEDLINE  
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[PMID]: 25449714
[Au] Autor:Ramsey TL; Brennan MD
[Ad] Address:SureGene, LLC, 600 Envoy Circle, Louisville, KY 40299, USA.
[Ti] Title:Glucagon-like peptide 1 receptor (GLP1R) haplotypes correlate with altered response to multiple antipsychotics in the CATIE trial.
[So] Source:Schizophr Res;160(1-3):73-9, 2014 Dec.
[Is] ISSN:1573-2509
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Glucagon-like peptide 1 receptor (GLP1R) signaling has been shown to have antipsychotic properties in animal models and to impact glucose-dependent insulin release, satiety, memory, and learning in man. Previous work has shown that two coding mutations (rs6923761 and rs1042044) are associated with altered insulin release and cortisol levels. We identified four frequently occurring haplotypes in Caucasians, haplotype 1 through haplotype 4, spanning exons 4-7 and containing the two coding variants. We analyzed response to antipsychotics, defined as predicted change in PANSS-Total (dPANSS) at 18months, in Caucasian subjects from the Clinical Antipsychotic Trial of Intervention Effectiveness treated with olanzapine (n=139), perphenazine (n=78), quetiapine (n=14), risperidone (n=143), and ziprasidone (n=90). Haplotype trend regression analysis revealed significant associations with dPANSS for olanzapine (best p=0.002), perphenazine (best p=0.01), quetiapine (best p=0.008), risperidone (best p=0.02), and ziprasidone (best p=0.007). We also evaluated genetic models for the two most common haplotypes. Haplotype 1 (uniquely including the rs1042044 [Leu(260)] allele) was associated with better response to olanzapine (p=0.002), and risperidone (p=0.006), and worse response to perphenazine (p=.03), and ziprasidone (p=0.003), with a recessive genetic model providing the best fit. Haplotype 2 (uniquely including the rs6923761 [Ser(168)] allele) was associated with better response to perphenazine (p=0.001) and worse response to olanzapine (p=.02), with a dominant genetic model providing the best fit. However, GLP1R haplotypes were not associated with antipsychotic-induced weight gain. These results link functional genetic variants in GLP1R to antipsychotic response.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review

  4 / 252801 MEDLINE  
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[PMID]: 25467983
[Au] Autor:Bharadwaj R; Peter CJ; Jiang Y; Roussos P; Vogel-Ciernia A; Shen EY; Mitchell AC; Mao W; Whittle C; Dincer A; Jakovcevski M; Pothula V; Rasmussen TP; Giakoumaki SG; Bitsios P; Sherif A; Gardner PD; Ernst P; Ghose S; Sklar P; Haroutunian V; Tamminga C; Myers RH; Futai K; Wood MA; Akbarian S
[Ad] Address:Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA....
[Ti] Title:Conserved Higher-Order Chromatin Regulates NMDA Receptor Gene Expression and Cognition.
[So] Source:Neuron;84(5):997-1008, 2014 Dec 3.
[Is] ISSN:1097-4199
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3' intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a "cargo" of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher-order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review

  5 / 252801 MEDLINE  
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[PMID]: 25420615
[Au] Autor:Vaucher P; Herzig D; Cardoso I; Herzog MH; Mangin P; Favrat B
[Ad] Address:Traffic Medicine and Psychology Unit, University Center of Legal Medicine, Lausanne-Geneva, University Hospital of Lausanne, Rue Saint-Martin 26, 1005 Lausanne, Switzerland. paul.vaucher@gmail.com.
[Ti] Title:The trail making test as a screening instrument for driving performance in older drivers; a translational research.
[So] Source:BMC Geriatr;14(1):123, 2014.
[Is] ISSN:1471-2318
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: In many countries, primary care physicians determine whether or not older drivers are fit to drive. Little, however, is known regarding the effects of cognitive decline on driving performance and the means to detect it. This study explores to what extent the trail making test (TMT) can provide indications to clinicians about their older patients' on-road driving performance in the context of cognitive decline. METHODS: This translational study was nested within a cohort study and an exploratory psychophysics study. The target population of interest was constituted of older drivers in the absence of important cognitive or physical disorders. We therefore recruited and tested 404 home-dwelling drivers, aged 70 years or more and in possession of valid drivers' licenses, who volunteered to participate in a driving refresher course. Forty-five drivers also agreed to undergo further testing at our lab. On-road driving performance was evaluated by instructors during a 45 minute validated open-road circuit. Drivers were classified as either being excellent, good, moderate, or poor depending on their score on a standardized evaluation of on-road driving performance. RESULTS: The area under the receiver operator curve for detecting poorly performing drivers was 0.668 (CI95% 0.558 to 0.778) for the TMT-A, and 0.662 (CI95% 0.542 to 0.783) for the TMT-B. TMT was related to contrast sensitivity, motion direction, orientation discrimination, working memory, verbal fluency, and literacy. Older patients with a TMT-A ≥ 54 seconds or a TMT-B ≥ 150 seconds have a threefold (CI95% 1.3 to 7.0) increased risk of performing poorly during the on-road evaluation. TMT had a sensitivity of 63.6%, a specificity of 64.9%, a positive predictive value of 9.5%, and a negative predictive value of 96.9%. CONCLUSION: In screening settings, the TMT would have clinicians uselessly consider driving cessation in nine drivers out of ten. Given the important negative impact this could have on older drivers, this study confirms the TMT not to be specific enough for clinicians to justify driving cessation without complementary investigations on driving behaviors.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1186/1471-2318-14-123

  6 / 252801 MEDLINE  
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[PMID]: 25438146
[Au] Autor:Juan MC; Mendez-Lopez M; Perez-Hernandez E; Albiol-Perez S
[Ad] Address:Instituto Universitario de Automática e Informática Industrial, Universitat Politècnica de València, Camino de Vera, s/n. 46022 Valencia, Spain....
[Ti] Title:Augmented Reality for the Assessment of Children's Spatial Memory in Real Settings.
[So] Source:PLoS One;9(12):e113751, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Short-term memory can be defined as the capacity for holding a small amount of information in mind in an active state for a short period of time. Although some instruments have been developed to study spatial short-term memory in real environments, there are no instruments that are specifically designed to assess visuospatial short-term memory in an attractive way to children. In this paper, we present the ARSM (Augmented Reality Spatial Memory) task, the first Augmented Reality task that involves a user's movement to assess spatial short-term memory in healthy children. The experimental procedure of the ARSM task was designed to assess the children's skill to retain visuospatial information. They were individually asked to remember the real place where augmented reality objects were located. The children (N = 76) were divided into two groups: preschool (5-6 year olds) and primary school (7-8 year olds). We found a significant improvement in ARSM task performance in the older group. The correlations between scores for the ARSM task and traditional procedures were significant. These traditional procedures were the Dot Matrix subtest for the assessment of visuospatial short-term memory of the computerized AWMA-2 battery and a parent's questionnaire about a child's everyday spatial memory. Hence, we suggest that the ARSM task has high verisimilitude with spatial short-term memory skills in real life. In addition, we evaluated the ARSM task's usability and perceived satisfaction. The study revealed that the younger children were more satisfied with the ARSM task. This novel instrument could be useful in detecting visuospatial short-term difficulties that affect specific developmental navigational disorders and/or school academic achievement.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113751

  7 / 252801 MEDLINE  
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[PMID]: 25438043
[Au] Autor:Kalpakidou AK; Allin MP; Walshe M; Giampietro V; McGuire PK; Rifkin L; Murray RM; Nosarti C
[Ad] Address:Department of Psychosis Studies, Institute of Psychiatry, King's Health Partners, King's College London, London, United Kingdom....
[Ti] Title:Functional neuroanatomy of executive function after neonatal brain injury in adults who were born very preterm.
[So] Source:PLoS One;9(12):e113975, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Individuals who were born very preterm (VPT; <33 gestational weeks) are at risk of experiencing deficits in tasks involving executive function in childhood and beyond. In addition, the type and severity of neonatal brain injury associated with very preterm birth may exert differential effects on executive functioning by altering its neuroanatomical substrates. Here we addressed this question by investigating with functional magnetic resonance imaging (fMRI) the haemodynamic response during executive-type processing using a phonological verbal fluency and a working memory task in VPT-born young adults who had experienced differing degrees of neonatal brain injury. 12 VPT individuals with a history of periventricular haemorrhage and ventricular dilatation (PVH+VD), 17 VPT individuals with a history of uncomplicated periventricular haemorrhage (UPVH), 13 VPT individuals with no history of neonatal brain injury and 17 controls received an MRI scan whilst completing a verbal fluency task with two cognitive loads ('easy' and 'hard' letters). Two groups of VPT individuals (PVH+VD; n = 10, UPVH; n = 8) performed an n-back task with three cognitive loads (1-, 2-, 3-back). Results demonstrated that VPT individuals displayed hyperactivation in frontal, temporal, and parietal cortices and in caudate nucleus, insula and thalamus compared to controls, as demands of the verbal fluency task increased, regardless of type of neonatal brain injury. On the other hand, during the n-back task and as working memory load increased, the PVH+VD group showed less engagement of the frontal cortex than the UPVH group. In conclusion, this study suggests that the functional neuroanatomy of different executive-type processes is altered following VPT birth and that neural activation associated with specific aspects of executive function (i.e., working memory) may be particularly sensitive to the extent of neonatal brain injury.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113975

  8 / 252801 MEDLINE  
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[PMID]: 25437848
[Au] Autor:Reichert CF; Maire M; Gabel V; Hofstetter M; Viola AU; Kolodyazhniy V; Strobel W; Goetz T; Bachmann V; Landolt HP; Cajochen C; Schmidt C
[Ad] Address:Centre for Chronobiology, Psychiatric Hospital of the University of Basel, 4012, Basel, Switzerland....
[Ti] Title:The Circadian Regulation of Sleep: Impact of a Functional ADA-Polymorphism and Its Association to Working Memory Improvements.
[So] Source:PLoS One;9(12):e113734, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working memory independent of the timing of the sleep episode within the 24-h cycle.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113734

  9 / 252801 MEDLINE  
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[PMID]: 25437002
[Au] Autor:PLOS ONE Staff
[Ti] Title:Correction: detecting memory and structure in human navigation patterns using markov chain models of varying order.
[So] Source:PLoS One;9(12):e114952, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:[This corrects the article DOI: 10.1371/journal.pone.0102070.].
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0114952

  10 / 252801 MEDLINE  
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[PMID]: 25436776
[Au] Autor:Dubois M; Le Joncour V; Tonon MC; Anouar Y; Proust F; Morin F; Gandolfo P; Joly F; Hilber P; Castel H
[Ad] Address:Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation (DC2N), Astrocyte and Vascular Niche, University of Rouen, Mont-Saint-Aignan, France; PRES Normandie Université, Institute of Research and Biomedical Innovation (IRIB), University of Rouen, Mont-Saint-Aignan, Fr...
[Ti] Title:Evaluation of the impact of the cancer therapy everolimus on the central nervous system in mice.
[So] Source:PLoS One;9(12):e113533, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1412
[Cu] Class update date: 141206
[Lr] Last revision date:141206
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0113533


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