ALBERT

Description: Organic Letters DOI: 10.1021/ol5019163

Description: Excitable media are spatially distributed systems characterized by their ability to propagate signals undamped over long distances. Wave propagation in excitable media has been modeled extensively both by continuous partial differential equations and by discrete cellular automata. Cellular automata are desirable because of their intuitive appeal and efficient digital implementation, but until now they have not served as reliable models because they have lacked two essential properties of excitable media. First, traveling waves show dispersion, that is, the speed of wave propagation into a recovering region depends on the time elapsed since the preceding wave passed through that region. Second, wave speed depends on wave front curvature: curved waves travel with normal velocities noticeably different from the plane-wave velocity. These deficiencies of cellular automation models are remedied by revising the classical rules of the excitation and recovery processes. The revised model shows curvature and dispersion effects comparable to those of continuous models, it predicts rotating spiral wave solutions in quantitative accord with the theory of continuous excitable media, and it is parameterized so that the spatial step size of the automation can be adjusted for finer resolution of traveling waves.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerhardt, M -- Schuster, H -- Tyson, J J -- New York, N.Y. -- Science. 1990 Mar 30;247(4950):1563-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Virginia Polytechnic Institute, State University, Blacksburg 24061.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2321017" target="_blank"〉PubMed〈/a〉

Description: The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279952/" 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/PMC4279952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gubin, Matthew M -- Zhang, Xiuli -- Schuster, Heiko -- Caron, Etienne -- Ward, Jeffrey P -- Noguchi, Takuro -- Ivanova, Yulia -- Hundal, Jasreet -- Arthur, Cora D -- Krebber, Willem-Jan -- Mulder, Gwenn E -- Toebes, Mireille -- Vesely, Matthew D -- Lam, Samuel S K -- Korman, Alan J -- Allison, James P -- Freeman, Gordon J -- Sharpe, Arlene H -- Pearce, Erika L -- Schumacher, Ton N -- Aebersold, Ruedi -- Rammensee, Hans-Georg -- Melief, Cornelis J M -- Mardis, Elaine R -- Gillanders, William E -- Artyomov, Maxim N -- Schreiber, Robert D -- P01 AI054456/AI/NIAID NIH HHS/ -- P30 AR048335/AR/NIAMS NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30 CA091842/CA/NCI NIH HHS/ -- P50 CA101942/CA/NCI NIH HHS/ -- R01 AI091965/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- R01 CA190700/CA/NCI NIH HHS/ -- R37 CA043059/CA/NCI NIH HHS/ -- T32 CA009547/CA/NCI NIH HHS/ -- T32 CA00954729/CA/NCI NIH HHS/ -- U01 CA141541/CA/NCI NIH HHS/ -- England -- Nature. 2014 Nov 27;515(7528):577-81. doi: 10.1038/nature13988.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; Department of Immunology, Institute of Cell Biology, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tubingen, Auf der Morgenstelle 15, 72076 Tubingen, Germany. ; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland. ; 1] Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [2] Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands. ; Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. ; Bristol-Myers Squibb, 700 Bay Road, Redwood City, California 94063, USA. ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, Zurich, 8093 Zurich, Switzerland. ; 1] ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands [2] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, The Netherlands. ; 1] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428507" target="_blank"〉PubMed〈/a〉

Description: Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic alpha-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of alpha-olefins, none of these catalytic enantioselective processes results in chain-extending carbon-carbon bond formation to the terminal carbon. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (〉95:5 enantiomer ratio), uses low loadings (1-2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947102/" 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/PMC3947102/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mlynarski, Scott N -- Schuster, Christopher H -- Morken, James P -- GM-59417/GM/NIGMS NIH HHS/ -- R01 GM059417/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jan 16;505(7483):386-90. doi: 10.1038/nature12781. Epub 2013 Dec 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24352229" target="_blank"〉PubMed〈/a〉