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[PMID]: 25246499
[Au] Autor:Devarajan P; Miska J; Lui JB; Swieboda D; Chen Z
[Ad] Address:Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33136; and....
[Ti] Title:Opposing Effects of CTLA4 Insufficiency on Regulatory versus Conventional T Cells in Autoimmunity Converge on Effector Memory in Target Tissue.
[So] Source:J Immunol;193(9):4368-80, 2014 Nov 1.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Quantitative variations in CTLA4 expression, because of genetic polymorphisms, are associated with various human autoimmune conditions, including type 1 diabetes (T1D). Extensive studies have demonstrated that CTLA4 is not only essential for the suppressive role of regulatory T cells (Treg) but also required for intrinsic control of conventional T (Tconv) cells. We report that a modest insufficiency of CTLA4 in mice, which mimics the effect of some human CTLA4 genetic polymorphisms, accompanied by a T1D-permissive MHC locus, was sufficient to induce juvenile-onset diabetes on an otherwise T1D-resistant genetic background. Reduction in CTLA4 levels had an unanticipated effect in promoting Treg function both in vivo and in vitro. It led to an increase in Treg memory in both lymphoid and nonlymphoid target tissue. Conversely, modulating CTLA4 by either RNA interference or Ab blockade promoted conventional effector memory T cell formation in the Tconv compartment. The CD4(+) conventional effector memory T cells, including those within target tissue, produced IL-17 or IFN-γ. Blocking IL-7 signaling reduced the Th17 autoimmune compartment but did not suppress the T1D induced by CTLA4 insufficiency. Enhanced effector memory formation in both Tconv and Treg lineages may underpin the apparently dichotomized impact of CTLA4 insufficiency on autoimmune pathogenesis. Therefore, although the presence of CTLA4 plays a critical role in controlling homeostasis of T cells, its quantitative variation may impose diverse or even opposing effects on distinct lineages of T cells, an optimal sum of which is necessary for preservation of T cell immunity while suppressing tissue damage.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1400876

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[PMID]: 25225671
[Au] Autor:McLaughlin KA; Gulati K; Richardson CC; Morgan D; Bodansky HJ; Feltbower RG; Christie MR
[Ad] Address:Division of Diabetes and Nutritional Sciences, Guy's Campus, King's College London, London SE1 1UL, United Kingdom; and....
[Ti] Title:HLA-DR4-Associated T and B Cell Responses to Specific Determinants on the IA-2 Autoantigen in Type 1 Diabetes.
[So] Source:J Immunol;193(9):4448-56, 2014 Nov 1.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Autoantibodies to IA-2 in type 1 diabetes are associated with HLA-DR4, suggesting influences of HLA-DR4-restricted T cells on IA-2-specific B cell responses. The aim of this study was to investigate possible T-B cell collaboration by determining whether autoantibodies to IA-2 epitopes are associated with T cell responses to IA-2 peptides presented by DR4. T cells secreting the cytokines IFN-γ and IL-10 in response to seven peptides known to elicit T cell responses in type 1 diabetes were quantified by cytokine ELISPOT in HLA-typed patients characterized for Abs to IA-2 epitopes. T cell responses were detected to all peptides tested, but only IL-10 responses to 841-860 and 853-872 peptides were associated with DR4. Phenotyping by RT-PCR of FACS-sorted CD45RO(hi) T cells secreting IL-10 in response to these two peptides indicated that these expressed GATA-3 or T-bet, but not FOXP3, consistent with these being Th2 or Th1 memory T cells rather than of regulatory phenotype. T cell responses to the same two peptides were also associated with specific Abs: those to 841-860 peptide with Abs to juxtamembrane epitopes, which appear early in prediabetes, and those to peptide 853-872 with Abs to an epitope located in the 831-862 central region of the IA-2 tyrosine phosphatase domain. Abs to juxtamembrane and central region constructs were both DR4 associated. This study identifies a region of focus for B and T cell responses to IA-2 in HLA-DR4 diabetic patients that may explain HLA associations of IA-2 autoantibodies, and this region may provide a target for future immune intervention to prevent disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1301902

  3 / 250616 MEDLINE  
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[PMID]: 24919843
[Au] Autor:Sun M; Shi H; Liu C; Liu J; Liu X; Sun Y
[Ti] Title:Construction and evaluation of a novel humanized HER2-specific chimeric receptor.
[So] Source:Breast Cancer Res;16(3):R61, 2014.
[Is] ISSN:1465-542X
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:INTRODUCTION: The human epidermal growth factor receptor 2 (HER2) represents one of the most studied tumor-associated antigens (TAAs) for cancer immunotherapy. The monoclonal antibody (mAb) trastuzumab has improved the outcomes of patients with HER2+ breast cancer. However, a large number of HER2+ tumors are not responsive to, or become resistant to, trastuzumab-based therapy, and thus more effective therapies targeting HER2 are needed. METHODS: HER2-specific T cells were generated by the transfer of genes that encode chimeric antigen receptor (CAR). Using a multistep overlap extension PCR method, we constructed a novel, humanized HER2 CAR-containing, chA21 single-chain variable fragment (scFv) region of antigen-specific mAb and T-cell intracellular signaling chains made up of CD28 and CD3ζ. An interferon γ and interleukin 2 enzyme-linked immunosorbent assay and a chromium-51 release assay were used to evaluate the antitumor immune response of CAR T cells in coculture with tumor cells. Furthermore, SKBR3 tumor-bearing nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice were treated with HER2 CAR T cells to evaluate antitumor activity. Human CD3+ T cell accumulation in tumor xenograft was detected by immunohistochemistry. RESULTS: chA21-28z CAR was successfully constructed, and both CD4+ and CD8+ T cells were transduced. The expanded HER2 CAR T cells expressed a central memory phenotype and specifically reacted against HER2+ tumor cell lines. Furthermore, the SKBR3 tumor xenograft model revealed that HER2 CAR T cells significantly inhibited tumor growth in vivo. Immunohistochemical analysis showed robust accumulation of human CD3+ T cells in regressing SKBR3 lesions. CONCLUSIONS: The results of this study show that novel chA21 scFv-based, HER2-specific CAR T cells not only recognized and killed HER2+ breast and ovarian cancer cells ex vivo but also induced regression of experimental breast cancer in vivo. Our data support further exploration of the HER2 CAR T-cell therapy for HER2-expressing cancers.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1186/bcr3674

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[PMID]: 23806713
[Au] Autor:Walton JC; Chen Z; Travers JB; Nelson RJ
[Ad] Address:Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. Electronic address: walton.315@osu.edu....
[Ti] Title:Exogenous melatonin reproduces the effects of short day lengths on hippocampal function in male white-footed mice, Peromyscus leucopus.
[So] Source:Neuroscience;248:403-13, 2013 Sep 17.
[Is] ISSN:1873-7544
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Photoperiodism is a biological phenomenon, common among organisms living outside of the tropics, by which environmental day length is used to ascertain the time of year to engage in seasonally-appropriate adaptations. White-footed mice (Peromyscus leucopus) are small photoperiodic rodents which display a suite of adaptive winter responses to short day lengths mediated by the extended duration of nightly melatonin secretion. Exposure to short days alters hippocampal dendritic morphology, impairs spatial learning and memory, and impairs hippocampal long-term potentiation (LTP). To determine the role of melatonin in these photoperiod-induced alterations of behavioral, neuroanatomical, and neurophysiological processes in this species, we implanted male mice subcutaneously with melatonin or empty Silastic capsules and exposed them to long or short day lengths. After 10weeks, mice were assessed for hippocampal LTP, tested for spatial learning and memory in the Barnes maze, and morphometric analysis of neurons in the hippocampus using Golgi staining. Extending the duration of melatonin exposure, by short-day exposure or via melatonin implants, impaired both Schaffer collateral LTP in the CA1 region of the hippocampus and spatial learning and memory, and altered neuronal morphology in all hippocampal regions. The current results demonstrate that chronic melatonin implants reproduce the effects of short days on the hippocampus and implicate melatonin signaling as a critical factor in day-length-induced changes in the structure and function of the hippocampus in a photoperiodic rodent.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review

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[PMID]: 25320614
[Au] Autor:Tajik-Parvinchi D; Wright L; Schachar R
[Ad] Address:Hospital for Sick Children, Department of Psychiatry, Toronto, Ontario.
[Ti] Title:Cognitive Rehabilitation for Attention Deficit/Hyperactivity Disorder (ADHD): Promises and Problems.
[So] Source:J Can Acad Child Adolesc Psychiatry;23(3):207-17, 2014 Sep.
[Is] ISSN:1719-8429
[Cp] Country of publication:Canada
[La] Language:eng
[Ab] Abstract:OBJECTIVE: Cognitive training entails the repeated exercise of a specific cognitive process over a period of time to improve performance on the trained task as well as on tasks that were not specifically trained (transfer effect). Cognitive training shows promise in remediating deficits in children with attention deficit/hyperactivity disorder (ADHD) - a disorder believed to stem from deficient cognitive processes - where the focus has been primarily on training working memory and attention. We discuss evidence from studies that have produced broad, limited, or no transfer effects with the goal of identifying factors that may be responsible for this heterogeneity. RESULTS: There are several implicit assumptions that appear to drive researchers' decisions regarding both the selection of cognitive abilities to train as well as the training tasks chosen to target those abilities. We identify these implicit assumptions and their weaknesses. We also draw attention to design limitations that may be contributing to lack of transfer. CONCLUSION: Although the overall pattern of findings from these studies is promising, the methodological and theoretical limitations associated with the literature limit conclusions about the efficacy of cognitive training as a rehabilitation method for ADHD. We hypothesize several suggestions that may improve training effects and summarize the evidence which led to our hypotheses.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Cu] Class update date: 141018
[Lr] Last revision date:141018
[Da] Date of entry for processing:141016
[St] Status:PubMed-not-MEDLINE

  6 / 250616 MEDLINE  
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[PMID]: 25200178
[Au] Autor:Orban de Xivry JJ; Shadmehr R
[Ad] Address:Institute of Information and Communication Technologies, Electronics and Applied Mathematics (ICTEAM) and Institute of Neuroscience (IoNS), Universit Catholique de Louvain, Avenue Georges Lemaitre, 4, 1348, Louvain-La-Neuve, Belgium, jj.orban@uclouvain.be.
[Ti] Title:Electrifying the motor engram: effects of tDCS on motor learning and control.
[So] Source:Exp Brain Res;232(11):3379-95, 2014 Nov.
[Is] ISSN:1432-1106
[Cp] Country of publication:Germany
[La] Language:eng
[Ab] Abstract:Learning to control our movements is accompanied by neuroplasticity of motor areas of the brain. The mechanisms of neuroplasticity are diverse and produce what is referred to as the motor engram, i.e., the neural trace of the motor memory. Transcranial direct current stimulation (tDCS) alters the neural and behavioral correlates of motor learning, but its precise influence on the motor engram is unknown. In this review, we summarize the effects of tDCS on neural activity and suggest a few key principles: (1) Firing rates are increased by anodal polarization and decreased by cathodal polarization, (2) anodal polarization strengthens newly formed associations, and (3) polarization modulates the memory of new/preferred firing patterns. With these principles in mind, we review the effects of tDCS on motor control, motor learning, and clinical applications. The increased spontaneous and evoked firing rates may account for the modulation of dexterity in non-learning tasks by tDCS. The facilitation of new association may account for the effect of tDCS on learning in sequence tasks while the ability of tDCS to strengthen memories of new firing patterns may underlie the effect of tDCS on consolidation of skills. We then describe the mechanisms of neuroplasticity of motor cortical areas and how they might be influenced by tDCS. We end with current challenges for the fields of brain stimulation and motor learning.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1007/s00221-014-4087-6

  7 / 250616 MEDLINE  
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[PMID]: 25320409
[Au] Autor:Watanabe T; Kitazawa R; Mizuno Y; Kuwahara N; Ito C; Sugita A; Haraguchi R; Kitazawa S
[Ad] Address:Department of Molecular Pathology, Ehime University Graduate School of Medicine , Shitsukawa, Toon City, Ehime 791-0295, Japan....
[Ti] Title:BOB.1-positive Classical Hodgkin's Lymphoma Carries Hypermethylation of Its Promoter as Epigenetic Marker of Gene-silencing Memory.
[So] Source:Acta Histochem Cytochem;47(3):125-31, 2014 Jun 28.
[Is] ISSN:0044-5991
[Cp] Country of publication:Japan
[La] Language:eng
[Ab] Abstract:Analysis of archival formalin-fixed, paraffin-embedded (FFPE) pathological specimens of three case of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) and three cases of classical Hodgkin lymphoma (CHL) revealed that hypermethylation of the BOB.1 gene promoter was exclusively observed in CHL. A discrepancy was observed, however, between the methylation status of the BOB.1 gene promoter and its expression in the EBV-positive mixed cellular CHL (MCCHL). Since MCCHL lacks the typical B-cell phenotype even in the presence of abundant BOB.1 transcription factors, functional activity of BOB.1 may be lost or reduced by a mechanism other than epigenetic gene silencing. When some tumor-suppressor gene products have lost their biological function, impact or significance of derepression of such genes may be little. Therefore, when interpreting immunohistochemical results for diagnostic or research purposes, it must be borne in mind that apparent positive immunostaining can merely be the result of chromatin remodeling and that such transient expression often has little functional significance. Any apparent positive immunohistochemical result needs to be interpreted carefully with the help of the hypermethylation status as a molecular marker of gene silencing memory.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Cu] Class update date: 141018
[Lr] Last revision date:141018
[Da] Date of entry for processing:141016
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1267/ahc.14012

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[PMID]: 25314272
[Au] Autor:Abrmoff MD; Wu X; Lee K; Tang L
[Ad] Address:Department of Ophthalmology and Visual Sciences, Stephen A Wynn Institute for Vision Research, Department of Biomedical Engineering, and Department of Electrical and Computer Engineering, University of Iowa, Iowa City, Iowa, United States of America; Iowa City Veterans Administration Medical Center,...
[Ti] Title:Subvoxel accurate graph search using non-euclidean graph space.
[So] Source:PLoS One;9(10):e107763, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Graph search is attractive for the quantitative analysis of volumetric medical images, and especially for layered tissues, because it allows globally optimal solutions in low-order polynomial time. However, because nodes of graphs typically encode evenly distributed voxels of the volume with arcs connecting orthogonally sampled voxels in Euclidean space, segmentation cannot achieve greater precision than a single unit, i.e. the distance between two adjoining nodes, and partial volume effects are ignored. We generalize the graph to non-Euclidean space by allowing non-equidistant spacing between nodes, so that subvoxel accurate segmentation is achievable. Because the number of nodes and edges in the graph remains the same, running time and memory use are similar, while all the advantages of graph search, including global optimality and computational efficiency, are retained. A deformation field calculated from the volume data adaptively changes regional node density so that node density varies with the inverse of the expected cost. We validated our approach using optical coherence tomography (OCT) images of the retina and 3-D MR of the arterial wall, and achieved statistically significant increased accuracy. Our approach allows improved accuracy in volume data acquired with the same hardware, and also, preserved accuracy with lower resolution, more cost-effective, image acquisition equipment. The method is not limited to any specific imaging modality and readily extensible to higher dimensions.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0107763

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[PMID]: 25317154
[Au] Autor:Jang SH; Kwon HG
[Ad] Address:Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Taegu, Republic of Korea.
[Ti] Title:Perspectives on the neural connectivity of the fornix in the human brain.
[So] Source:Neural Regen Res;9(15):1434-6, 2014 Aug 1.
[Is] ISSN:1673-5374
[Cp] Country of publication:India
[La] Language:eng
[Ab] Abstract:The fornix is involved in the transfer of information on episodic memory as a part of the Papez circuit. Diffusion tensor imaging enables to estimate the neural connectivity of the fornix. The anterior fornical body has high connectivity with the anterior commissure, and brain areas relevant to cholinergic nuclei (septal forebrain region and brainstem) and memory function (medial temporal lobe). In the normal subjects, by contrast, the posterior fornical body has connectivity with the cerebral cortex and brainstem through the splenium of the corpus callosum. We believe that knowledge of the neural connectivity of the fornix would be helpful in investigation of the neural network associated with memory and recovery mechanisms following injury of the fornix.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1410
[Cu] Class update date: 141018
[Lr] Last revision date:141018
[Da] Date of entry for processing:141015
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.4103/1673-5374.139459

  10 / 250616 MEDLINE  
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[PMID]: 25317334
[Au] Autor:Pollack SM; Jones RL; Farrar EA; Lai IP; Lee SM; Cao J; Pillarisetty VG; Hoch BL; Gullett A; Bleakley M; Conrad EU; Eary JF; Shibuya KC; Warren EH; Carstens JN; Heimfeld S; Riddell SR; Yee C
[Ad] Address:Clinical Research Division, D3-100 Fred Hutchinson Cancer Research Center, 1100 Fairview Ave, Seattle, WA 98109 USA ; Department of Medicine, University of Washington, Seattle, WA USA....
[Ti] Title:Tetramer guided, cell sorter assisted production of clinical grade autologous NY-ESO-1 specific CD8(+) T cells.
[So] Source:J Immunother Cancer;2(1):36, 2014.
[Is] ISSN:2051-1426
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Adoptive T cell therapy represents an attractive modality for the treatment of patients with cancer. Peripheral blood mononuclear cells have been used as a source of antigen specific T cells but the very low frequency of T cells recognizing commonly expressed antigens such as NY-ESO-1 limit the applicability of this approach to other solid tumors. To overcome this, we tested a strategy combining IL-21 modulation during in vitro stimulation with first-in-class use of tetramer-guided cell sorting to generate NY-ESO-1 specific cytotoxic T lymphocytes (CTL). METHODS: CTL generation was evaluated in 6 patients with NY-ESO-1 positive sarcomas, under clinical manufacturing conditions and characterized for phenotypic and functional properties. RESULTS: Following in vitro stimulation, T cells stained with NY-ESO-1 tetramer were enriched from frequencies as low as 0.4% to >90% after single pass through a clinical grade sorter. NY-ESO-1 specific T cells were generated from all 6 patients. The final products expanded on average 1200-fold to a total of 36 billion cells, were oligoclonal and contained 67-97% CD8(+), tetramer(+) T cells with a memory phenotype that recognized endogenous NY-ESO-1. CONCLUSION: This study represents the first series using tetramer-guided cell sorting to generate T cells for adoptive therapy. This approach, when used to target more broadly expressed tumor antigens such as WT-1 and additional Cancer-Testis antigens will enhance the scope and feasibility of adoptive T cell therapy.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Cu] Class update date: 141018
[Lr] Last revision date:141018
[Da] Date of entry for processing:141015
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.1186/s40425-014-0036-y


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