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[PMID]: 25261477
[Au] Autor:Donnelly RP; Loftus RM; Keating SE; Liou KT; Biron CA; Gardiner CM; Finlay DK
[Ad] Address:School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland;...
[Ti] Title:mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function.
[So] Source:J Immunol;193(9):4477-84, 2014 Nov 1.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of NK cells, lymphocytes that play key roles in antiviral and antitumor immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell proinflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFN-γ, which is important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, upregulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFN-γ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:AIM; IM
[St] Status:In-Data-Review
[do] DOI:10.4049/jimmunol.1401558

  2 / 443915 MEDLINE  
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[PMID]: 25320488
[Au] Autor:Hayatbakhsh MR; Khara H; Movahed R; Sayadborani M; Rohi JD; Ahmadnezhad M; Rahbar M; Rad AS
[Ad] Address:Young Researcher Club, Islamic Azad University, Lahijan Branch, P.O. Box: 1616, Tehran, Iran....
[Ti] Title:Haematological characteristics associated with parasitism in bream, Abramis brama orientalis.
[So] Source:J Parasit Dis;38(4):383-8, 2014 Dec.
[Is] ISSN:0971-7196
[Cp] Country of publication:India
[La] Language:eng
[Ab] Abstract:A parasitological investigation was done on 175 specimens. Infections of A. brama orientalis were analyzed according to the age and sex. The fish also were examined for evaluation changes of haematological parameters in relation to parasitic infection. Four parasites were found, including-Caryophyllaeus laticeps and Ligula intestinalis (Cestoda), Diplostomum spathaceum (Platyhelminthes) and Trichodina sp. (Ciliophora). Among identified parasites maximum prevalence and mean intensity were related to Ligula intestinalis and Caryophyllaeus laticeps respectively. The values of prevalence and mean intensity showed significant differences among ages. Our results revealed prevalence, mean intensity and abundance had not significant difference between males and females. Parasite infection provoked reduction (P<0.05) in haematocrit, mean cell volume and lymphocyte. On the other hand, significant increase (P<0.05) in white blood cell (WBC), mean cell haemoglobin concentration and neutrophil in blood of infected fish was observed. Significant differences were detected for the WBC, lymphocyte and neutrophil (infected versus uninfected by Trichodina sp., Diplostomum spathaceum and Caryophyllaeus laticeps). In addition to WBC and lymphocytes, significant change was observed for the haemoglobin (Hb) (infected versus uninfected by Ligula intestinalis).
[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:10.1007/s12639-013-0256-y

  3 / 443915 MEDLINE  
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[PMID]: 25320633
[Au] Autor:Lafeuillade A; Assi A; Poggi C; Bresson-Cuquemelle C; Jullian E; Tamalet C
[Ad] Address:Department of Infectious Diseases, Sainte Musse, General Hospital, 54 rue Henri Sainte Claire Deville, 83100 Toulon, France....
[Ti] Title:Failure of combined antiretroviral therapy intensification with maraviroc and raltegravir in chronically HIV-1 infected patients to reduce the viral reservoir: the IntensHIV randomized trial.
[So] Source:AIDS Res Ther;11(1):33, 2014.
[Is] ISSN:1742-6405
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Ongoing HIV-1 replication in lymphoid cells is one explanation of the persistence of HIV-1 reservoirs despite highly active antiretroviral therapy (cART). We tested the potential of cART intensification by Maraviroc plus Raltegravir to decrease proviral HIV-1 DNA levels in lymphoid cells during a randomized trial. PATIENTS AND METHODS: We randomly assigned for 48weeks 22 patients to continue their current first line regimen of Truvada plus Kaletra or intensify it with Maraviroc and Raltegravir. The primary objective was to obtain a 50% decrease in proviral HIV-1 DNA levels in lymphoid cells with intensification. Blood samples were drawn at W-2, W0, W2, W4, W12, W24 and W48. Plasma viremia, cellular proviral DNA and cellular RNA, 2-LTR circles and lymphocytes subsets were assayed using validated methods. Patients in the intensified group underwent a gut biopsy at baseline and W48 to measure proviral DNA levels. Statistical analysis used parametric and non-parametric tests. RESULTS: Ten patients in each arm completed the trial. The 2 populations were comparable at baseline. No change in the reservoir size was observed in the intensified arm compared to the control arm measured in peripheral blood mononuclear cells (PBMCs). No change in the reservoir size was observed in gut proviral DNA in the intensified arm. In this group, no increase in 2-LTR circles was observed as early as 2weeks after intensification and no change was found in residual plasma RNA levels measured by the single copy assay. However, a decrease in CD8(+) T cells activation was observed at 24 and 48weeks, as well as in PBMCs HIV-1 RNA levels. CONCLUSION: We conclude that the intensification of a Protease Inhibitor regimen with Maraviroc and Raltegravir does not impact the blood proviral DNA reservoir of HIV but can decrease the cell-associated HIV RNA, the CD8 activation and has a possible impact on rectal proviral HIV DNA in some patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier number NCT00935480.
[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:10.1186/1742-6405-11-33

  4 / 443915 MEDLINE  
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[PMID]: 25313857
[Au] Autor:Vu DM; Tai A; Tatro JB; Karas RH; Huber BT; Beasley D
[Ad] Address:Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, United States of America....
[Ti] Title:γδT Cells Are Prevalent in the Proximal Aorta and Drive Nascent Atherosclerotic Lesion Progression and Neutrophilia in Hypercholesterolemic Mice.
[So] Source:PLoS One;9(10):e109416, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Unique innate immunity-linked γδT cells have been seen in early human artery lesions, but their role in lesion development has received little attention. Here we investigated whether γδT cells modulate atherogenesis in apolipoprotein E-deficient (ApoE KO) mice. We found that γδT cell numbers were markedly increased in the proximal aorta of ApoE-deficient vs. wild-type mice during early atherogenesis, particularly in the aortic root and arch, where they comprised most of the T cells and lesion progression is most rapid. γδT cells infiltrated intimal lesions in ApoE KO mice, but only the adventitia in wild-type mice, and were more prevalent than CD4+ T cells in early nascent lesions, as evaluated by en face confocal microscopy. These aortic γδT cells produced IL-17, but not IFN-γ, analyzed by ex vivo FACS. Furthermore, aortic arch lipid accumulation correlated strongly with abundance of IL-17-expressing splenic γδT cells in individual ApoE KO mice. To investigate the role of these γδT cells in early atherogenesis, we analyzed ApoE/γδT double knockout (DKO) compared to ApoE KO mice. We observed reduced early intimal lipid accumulation at sites of nascent lesion formation, both in chow-fed (by 40%) and Western diet-fed (by 44%) ApoE/γδT DKO mice. In addition, circulating neutrophils were drastically reduced in these DKO mice on Western diet, while expansion of inflammatory monocytes and splenic Th1 or Th17 lymphocytes was not affected. These data reveal, for the first time, a pathogenic role of γδT cells in early atherogenesis in ApoE KO mice, by mechanisms likely to involve their IL-17 production and induction of neutrophilia. Targeting γδT cells thus might offer therapeutic benefit in atherosclerosis or other inflammatory vascular diseases.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0109416

  5 / 443915 MEDLINE  
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[PMID]: 25317396
[Au] Autor:Khadanga S; Solomon B; Dittus K
[Ad] Address:Department of Medicine, University of Vermont, Vermont, USA.
[Ti] Title:Hemophagocytic Lymphohistiocytosis (HLH) Associated with T-Cell Lymphomas: Broadening our Differential for Fever of Unknown Origin.
[So] Source:N Am J Med Sci;6(9):484-6, 2014 Sep.
[Is] ISSN:2250-1541
[Cp] Country of publication:India
[La] Language:eng
[Ab] Abstract:CONTEXT: Hemophagocytic lymphohistiocytosis (HLH), due to the excessive activity of histiocytes and lymphocytes, is a rare but aggressive disease that typically occurs in infancy but can be seen in all ages. If left untreated, patients with HLH may live for only a few months and die from multi-organ failure. CASE REPORT: We present two cases of HLH diagnosis. Fever, spleen, and hepatic abnormalities were noted in both cases. CONCLUSION: Early diagnosis is the key and these two cases of similar etiology highlight how fever of unknown origin should force us to broaden our differential.
[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:10.4103/1947-2714.141656

  6 / 443915 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

  7 / 443915 MEDLINE  
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[PMID]: 25313718
[Au] Autor:Ramu Y; Xu Y; Shin HG; Lu Z
[Ad] Address:Department of Physiology, Perelman School of Medicine, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States....
[Ti] Title:Counteracting suppression of CFTR and voltage-gated K(+) channels by a bacterial pathogenic factor with the natural product tannic acid.
[So] Source:Elife;3, 2014.
[Is] ISSN:2050-084X
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause recurring bacterial infection in CF patients' lungs. However, the severity of CF lung disease correlates poorly with genotype. Antibiotic treatment helps dramatically prolong patients' life. The lung disease generally determines prognosis and causes most morbidity and mortality; early control of infections is thus critical. Staphylococcus aureus is a main cause of early infection in CF lungs. It secretes sphingomyelinase (SMase) C that can suppress CFTR activity. SMase C also inhibits voltage-gated K(+) channels in lymphocytes; inhibition of these channels causes immunosuppression. SMase C's pathogenicity is further illustrated by the demonstration that once Bacillus anthracis is engineered to express high levels of SMase C, the resulting mutant can evade the host immunity elicited by a live vaccine because additional pathogenic mechanisms are created. By screening a chemical library, we find that the natural product tannic acid is an SMase C antidote.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.7554/eLife.03683

  8 / 443915 MEDLINE  
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[PMID]: 25304728
[Au] Autor:Forget MA; Malu S; Liu H; Toth C; Maiti S; Kale C; Haymaker C; Bernatchez C; Huls H; Wang E; Marincola FM; Hwu P; Cooper LJ; Radvanyi LG
[Ad] Address:*Department of Melanoma Medical Oncology Division of Pediatrics, MD Anderson Cancer Center, Houston, TX Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD ∥Lion Biotechnologies, Woodland Hills, CA Sidra Medical and Research Hospital, Doha, Qatar.
[Ti] Title:Activation and Propagation of Tumor-infiltrating Lymphocytes on Clinical-grade Designer Artificial Antigen-presenting Cells for Adoptive Immunotherapy of Melanoma.
[So] Source:J Immunother;37(9):448-60, 2014 Nov-Dec.
[Is] ISSN:1537-4513
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) is a therapy for metastatic melanoma with response rates of up to 50%. However, the generation of the TIL transfer product is challenging, requiring pooled allogeneic normal donor peripheral blood mononuclear cells (PBMC) used in vitro as "feeders" to support a rapid-expansion protocol. Here, we optimized a platform to propagate TIL to a clinical scale using K562 cells genetically modified to express costimulatory molecules such as CD86, CD137-ligand, and membrane-bound IL-15 to function as artificial antigen-presenting cells (aAPC) as an alternative to using PBMC feeders. EXPERIMENTAL DESIGN: We used aAPC or γ-irradiated PBMC feeders to propagate TIL and measured rates of expansion. The activation and differentiation state was evaluated by flow cytometry and differential gene expression analyses. Clonal diversity was assessed on the basis of the pattern of T-cell receptor usage. T-cell effector function was measured by evaluation of cytotoxic granule content and killing of target cells. RESULTS: The aAPC propagated TIL at numbers equivalent to that found with PBMC feeders, whereas increasing the frequency of CD8 T-cell expansion with a comparable effector-memory phenotype. mRNA profiling revealed an upregulation of genes in the Wnt and stem-cell pathways with the aAPC. The aAPC platform did not skew clonal diversity, and CD8 T cells showed comparable antitumor function as those expanded with PBMC feeders. CONCLUSIONS: TIL can be rapidly expanded with aAPC to clinical scale generating T cells with similar phenotypic and effector profiles as with PBMC feeders. These data support the clinical application of aAPC to manufacture TIL for the treatment of melanoma.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1097/CJI.0000000000000056

  9 / 443915 MEDLINE  
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[PMID]: 25286182
[Au] Autor:Meyer Zu Hrste G; Cordes S; Mausberg AK; Zozulya AL; Wessig C; Sparwasser T; Mathys C; Wiendl H; Hartung HP; Kieseier BC
[Ad] Address:Department of Neurology, Heinrich-Heine-University, Medical Faculty, Dsseldorf, Germany....
[Ti] Title:FoxP3+ Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies.
[So] Source:PLoS One;9(10):e108756, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0108756

  10 / 443915 MEDLINE  
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[PMID]: 25286160
[Au] Autor:Singh RS; Kaur HP; Singh J
[Ad] Address:Carbohydrate and Protein Biotechnology Laboratory, Department of Biotechnology, Punjabi University, Patiala, Punjab, India.
[Ti] Title:Purification and Characterization of a Mucin Specific Mycelial Lectin from Aspergillus gorakhpurensis: Application for Mitogenic and Antimicrobial Activity.
[So] Source:PLoS One;9(10):e109265, 2014.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Lectins are carbohydrate binding proteins or glycoproteins that bind reversibly to specific carbohydrates present on the apposing cells, which are responsible for their ability to agglutinate red blood cells, lymphocytes, fibroblasts, etc. Interest in lectins has been intensified due to their carbohydrate specificity as they can be valuable reagents for the investigation of cell surface sugars, purification and characterization of glycoproteins. The present study reports the purification, characterization and evaluation of mitogenic and antimicrobial potential of a mycelial lectin from Aspergillus gorakhpurensis. METHODS: Affinity chromatography on mucin-sepharose column was carried out for purification of Aspergillus gorakhpurensis lectin. The lectin was characterized for physico-chemical parameters. Mitogenic potential of the lectin was evaluated against splenocytes of Swiss albino mice by MTT assay. Antimicrobial activity of the purified lectin has also been evaluated by disc diffusion assay. RESULTS: Single-step affinity purification resulted in 18.6-fold purification of the mycelial lectin. The molecular mass of the lectin was found to be 70 kDa and it was composed of two subunits of 34.8 kDa as determined by gel filtration chromatography, SDS-PAGE and MALDI-TOF analysis. pH optima of the lectin was found to be 6.5-9.5, while optimum temperature for lectin activity was 20-30C. Lectin was stable within a pH range of 7.0-10.5 and showed fair thermostability. EDTA did not affect lectin activity whereas it was found susceptible to the denaturants tested. MTT assay revealed strong mitogenic potential of A. gorakhpurensis lectin at a concentration upto 150 g/mL. Antimicrobial activity assay showed its potent antibacterial activity against Bacillus cereus, Staphylococcous aureus and Escherichia coli and marginal antifungal activity against Saccharomyces cerevisiae. CONCLUSION: This is the first report on the mitogenic and antimicrobial potential of Aspergillus gorakhpurensis lectin. The results will provide useful guidelines for further research in clinical applications of this lectin.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1410
[Js] Journal subset:IM
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pone.0109265


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