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  • 1
    Publication Date: 2003-04-12
    Description: The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778341/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778341/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Joseph C -- Bevan, Michael J -- AI 19335/AI/NIAID NIH HHS/ -- R01 AI019335/AI/NIAID NIH HHS/ -- R01 AI019335-19/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2003 Apr 11;300(5617):339-42.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and the Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12690202" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; CD8-Positive T-Lymphocytes/*immunology/transplantation ; Cytotoxicity, Immunologic ; Genes, MHC Class II ; Immunization ; *Immunologic Memory ; Interferon-gamma/biosynthesis ; Listeria monocytogenes/genetics/immunology ; Listeriosis/*immunology ; Mice ; Mice, Inbred C57BL ; Ovalbumin/biosynthesis/genetics/immunology ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Helper-Inducer/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2001-08-25
    Description: In mammals, the canonical nuclear factor kappaB (NF-kappaB) signaling pathway activated in response to infections is based on degradation of IkappaB inhibitors. This pathway depends on the IkappaB kinase (IKK), which contains two catalytic subunits, IKKalpha and IKKbeta. IKKbeta is essential for inducible IkappaB phosphorylation and degradation, whereas IKKalpha is not. Here we show that IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappaB2 (p100) precursor. IKKalpha preferentially phosphorylates NF-kappaB2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK). IKKalpha is therefore a pivotal component of a second NF-kappaB activation pathway based on regulated NF-kappaB2 processing rather than IkappaB degradation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Senftleben, U -- Cao, Y -- Xiao, G -- Greten, F R -- Krahn, G -- Bonizzi, G -- Chen, Y -- Hu, Y -- Fong, A -- Sun, S C -- Karin, M -- AI434477/AI/NIAID NIH HHS/ -- AI45045/AI/NIAID NIH HHS/ -- ESO4151/ES/NIEHS NIH HHS/ -- New York, N.Y. -- Science. 2001 Aug 24;293(5534):1495-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11520989" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/immunology/*physiology ; Bone Marrow Cells/metabolism ; Evolution, Molecular ; Female ; Gene Expression Regulation ; Germinal Center ; I-kappa B Kinase ; I-kappa B Proteins/metabolism ; Immunoglobulin D/analysis ; Lipopolysaccharides/pharmacology ; Lymph Nodes/cytology/immunology ; Lymphoid Tissue/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/*metabolism ; NF-kappa B p52 Subunit ; Phosphorylation ; Protein Processing, Post-Translational ; Protein-Serine-Threonine Kinases/*metabolism ; Radiation Chimera ; Recombinant Proteins/metabolism ; *Signal Transduction ; Spleen/cytology/immunology ; Transcription, Genetic ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2009-01-13
    Description: In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674434/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674434/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Joseph C -- Beilke, Joshua N -- Lanier, Lewis L -- AI068129/AI/NIAID NIH HHS/ -- R01 AI068129/AI/NIAID NIH HHS/ -- R01 AI068129-09/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jan 29;457(7229):557-61. doi: 10.1038/nature07665. Epub 2009 Jan 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19136945" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics ; Adoptive Transfer ; Animals ; Cell Proliferation ; Immunologic Memory/*immunology ; Killer Cells, Natural/*cytology/*immunology ; Lymphoid Tissue/immunology ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; *Models, Immunological ; Muromegalovirus/immunology/physiology ; Phenotype ; T-Lymphocytes, Cytotoxic/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2012-01-28
    Description: Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Prahallad, Anirudh -- Sun, Chong -- Huang, Sidong -- Di Nicolantonio, Federica -- Salazar, Ramon -- Zecchin, Davide -- Beijersbergen, Roderick L -- Bardelli, Alberto -- Bernards, Rene -- England -- Nature. 2012 Jan 26;483(7387):100-3. doi: 10.1038/nature10868.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Carcinogenesis, Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22281684" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cetuximab ; Colorectal Neoplasms/*drug therapy/*enzymology/genetics/pathology ; Drug Resistance, Neoplasm/*drug effects ; Drug Synergism ; Enzyme Activation/drug effects ; Erlotinib Hydrochloride ; Feedback, Physiological/*drug effects ; Female ; HEK293 Cells ; Humans ; Indoles/pharmacology/therapeutic use ; Melanoma/drug therapy/metabolism ; Mice ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; Proto-Oncogene Proteins B-raf/*antagonists & ; inhibitors/chemistry/*genetics/metabolism ; Quinazolines/pharmacology/therapeutic use ; RNA Interference ; Receptor, Epidermal Growth Factor/*agonists/antagonists & inhibitors/metabolism ; Sulfonamides/pharmacology/therapeutic use ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2013-01-22
    Description: The non-canonical NF-kappaB pathway forms a major arm of NF-kappaB signalling that mediates important biological functions, including lymphoid organogenesis, B-lymphocyte function, and cell growth and survival. Activation of the non-canonical NF-kappaB pathway involves degradation of an inhibitory protein, TNF receptor-associated factor 3 (TRAF3), but how this signalling event is controlled is still unknown. Here we have identified the deubiquitinase OTUD7B as a pivotal regulator of the non-canonical NF-kappaB pathway. OTUD7B deficiency in mice has no appreciable effect on canonical NF-kappaB activation but causes hyperactivation of non-canonical NF-kappaB. In response to non-canonical NF-kappaB stimuli, OTUD7B binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant non-canonical NF-kappaB activation. Consequently, the OTUD7B deficiency results in B-cell hyper-responsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defence ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish OTUD7B as a crucial regulator of signal-induced non-canonical NF-kappaB activation and indicate a mechanism of immune regulation that involves OTUD7B-mediated deubiquitination and stabilization of TRAF3.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578967/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578967/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Hongbo -- Brittain, George C -- Chang, Jae-Hoon -- Puebla-Osorio, Nahum -- Jin, Jin -- Zal, Anna -- Xiao, Yichuan -- Cheng, Xuhong -- Chang, Mikyoung -- Fu, Yang-Xin -- Zal, Tomasz -- Zhu, Chengming -- Sun, Shao-Cong -- AI057555/AI/NIAID NIH HHS/ -- AI064639/AI/NIAID NIH HHS/ -- CA137059/CA/NCI NIH HHS/ -- GM84459/GM/NIGMS NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA137059/CA/NCI NIH HHS/ -- R01 GM084459/GM/NIGMS NIH HHS/ -- T32 CA009598/CA/NCI NIH HHS/ -- T32CA009598/CA/NCI NIH HHS/ -- England -- Nature. 2013 Feb 21;494(7437):371-4. doi: 10.1038/nature11831. Epub 2013 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23334419" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/immunology/metabolism ; Bacteria/immunology ; Cells, Cultured ; Endopeptidases/deficiency/genetics/*metabolism ; Female ; Fibroblasts ; HEK293 Cells ; Homeostasis ; Humans ; Intestines/immunology ; Male ; Mice ; NF-kappa B/*metabolism ; Proteolysis ; Receptors, Cell Surface/metabolism ; TNF Receptor-Associated Factor 3/*metabolism ; *Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2014-03-29
    Description: Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-beta signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-beta (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-beta results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-beta becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-beta signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Chong -- Wang, Liqin -- Huang, Sidong -- Heynen, Guus J J E -- Prahallad, Anirudh -- Robert, Caroline -- Haanen, John -- Blank, Christian -- Wesseling, Jelle -- Willems, Stefan M -- Zecchin, Davide -- Hobor, Sebastijan -- Bajpe, Prashanth K -- Lieftink, Cor -- Mateus, Christina -- Vagner, Stephan -- Grernrum, Wipawadee -- Hofland, Ingrid -- Schlicker, Andreas -- Wessels, Lodewyk F A -- Beijersbergen, Roderick L -- Bardelli, Alberto -- Di Nicolantonio, Federica -- Eggermont, Alexander M M -- Bernards, Rene -- MOP-130540/Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Apr 3;508(7494):118-22. doi: 10.1038/nature13121. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2]. ; 1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2] Department of Biochemistry, The Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, Quebec H3G 1Y6, Canada [3]. ; Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. ; Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France. ; Division of Medical Oncology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. ; Division of Pathology, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. ; 1] Division of Molecular Carcinogenesis, Cancer Systems Biology Centre and Cancer Genomics Centre Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands [2] Department of Pathology, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. ; 1] University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy [2] Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy. ; Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy. ; 1] University of Torino, Department of Oncology, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy [2] Candiolo Cancer Institute - FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy [3] FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670642" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*administration & dosage/*pharmacology ; Cell Aging/drug effects ; Cell Proliferation/drug effects ; Drug Resistance, Neoplasm/drug effects/genetics ; Female ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Library ; Humans ; Indoles/administration & dosage/pharmacology ; Melanoma/*drug therapy/enzymology/genetics/pathology ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; Protein Kinase Inhibitors/*administration & dosage/*pharmacology ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/*genetics/metabolism ; RNA, Small Interfering ; Receptor Protein-Tyrosine Kinases/biosynthesis/genetics/metabolism ; Receptor, Epidermal Growth Factor/biosynthesis/genetics/metabolism ; Receptor, Platelet-Derived Growth Factor beta/biosynthesis/genetics/metabolism ; SOXE Transcription Factors/deficiency/genetics ; Signal Transduction/drug effects ; Sulfonamides/administration & dosage/pharmacology ; Transforming Growth Factor beta/metabolism/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2013-12-20
    Description: Currently, there is little evidence for a notable role of the vertebrate microRNA (miRNA) system in the pathogenesis of RNA viruses. This is primarily attributed to the ease with which these viruses mutate to disrupt recognition and growth suppression by host miRNAs. Here we report that the haematopoietic-cell-specific miRNA miR-142-3p potently restricts the replication of the mosquito-borne North American eastern equine encephalitis virus in myeloid-lineage cells by binding to sites in the 3' non-translated region of its RNA genome. However, by limiting myeloid cell tropism and consequent innate immunity induction, this restriction directly promotes neurologic disease manifestations characteristic of eastern equine encephalitis virus infection in humans. Furthermore, the region containing the miR-142-3p binding sites is essential for efficient virus infection of mosquito vectors. We propose that RNA viruses can adapt to use antiviral properties of vertebrate miRNAs to limit replication in particular cell types and that this restriction can lead to exacerbation of disease severity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349380/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349380/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trobaugh, Derek W -- Gardner, Christina L -- Sun, Chengqun -- Haddow, Andrew D -- Wang, Eryu -- Chapnik, Elik -- Mildner, Alexander -- Weaver, Scott C -- Ryman, Kate D -- Klimstra, William B -- AI049820-10/AI/NIAID NIH HHS/ -- AI060525-08/AI/NIAID NIH HHS/ -- AI083383/AI/NIAID NIH HHS/ -- AI095436/AI/NIAID NIH HHS/ -- R01 AI083383/AI/NIAID NIH HHS/ -- R01 AI095436/AI/NIAID NIH HHS/ -- T32 AI060525/AI/NIAID NIH HHS/ -- U54 AI081680/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):245-8. doi: 10.1038/nature12869. Epub 2013 Dec 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Vaccine Research and Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Institute for Human Infections and Immunity, Center for Biodefense and Emerging Infectious Diseases, and Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555, USA. ; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel. ; Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24352241" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Alphavirus Infections/immunology/pathology/virology ; Animals ; Binding Sites/genetics ; Cell Line ; Cricetinae ; Culicidae/virology ; Disease Models, Animal ; Encephalitis Virus, Eastern Equine/genetics/growth & ; development/*immunology/*pathogenicity ; Female ; *Host-Pathogen Interactions/immunology ; *Immune Evasion/genetics ; Immunity, Innate/genetics/*immunology ; Insect Vectors/virology ; Male ; Mice ; MicroRNAs/*genetics/metabolism ; Myeloid Cells/immunology/virology ; Organ Specificity ; Virus Replication/genetics/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2016-03-17
    Description: CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Wei -- Bai, Yibing -- Xiong, Ying -- Zhang, Jin -- Chen, Shuokai -- Zheng, Xiaojun -- Meng, Xiangbo -- Li, Lunyi -- Wang, Jing -- Xu, Chenguang -- Yan, Chengsong -- Wang, Lijuan -- Chang, Catharine C Y -- Chang, Ta-Yuan -- Zhang, Ti -- Zhou, Penghui -- Song, Bao-Liang -- Liu, Wanli -- Sun, Shao-cong -- Liu, Xiaolong -- Li, Bo-liang -- Xu, Chenqi -- HL 60306./HL/NHLBI NIH HHS/ -- R01 HL060306/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Mar 31;531(7596):651-5. doi: 10.1038/nature17412. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Haven 03755, USA. ; Rheumatology and Immunology Department of ChangZheng Hospital, Second Military Medical University, Shanghai 200433, China. ; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. ; College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China. ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982734" target="_blank"〉PubMed〈/a〉
    Keywords: Acetates/*pharmacology/therapeutic use ; Acetyl-CoA C-Acetyltransferase/antagonists & ; inhibitors/deficiency/genetics/metabolism ; Animals ; Atherosclerosis/drug therapy ; CD8-Positive T-Lymphocytes/*drug effects/*immunology/metabolism ; Cell Membrane/drug effects/metabolism ; Cholesterol/*metabolism ; Esterification/drug effects ; Female ; Immunological Synapses/drug effects/immunology/metabolism ; Immunotherapy/*methods ; Male ; Melanoma/*drug therapy/*immunology/metabolism/pathology ; Mice ; Programmed Cell Death 1 Receptor/antagonists & inhibitors/immunology ; Receptors, Antigen, T-Cell/immunology/metabolism ; Signal Transduction/drug effects ; Sulfonic Acids/*pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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