ALBERT

Description: Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chao -- Spevak, Wayne -- Zhang, Ying -- Burton, Elizabeth A -- Ma, Yan -- Habets, Gaston -- Zhang, Jiazhong -- Lin, Jack -- Ewing, Todd -- Matusow, Bernice -- Tsang, Garson -- Marimuthu, Adhirai -- Cho, Hanna -- Wu, Guoxian -- Wang, Weiru -- Fong, Daniel -- Nguyen, Hoa -- Shi, Songyuan -- Womack, Patrick -- Nespi, Marika -- Shellooe, Rafe -- Carias, Heidi -- Powell, Ben -- Light, Emily -- Sanftner, Laura -- Walters, Jason -- Tsai, James -- West, Brian L -- Visor, Gary -- Rezaei, Hamid -- Lin, Paul S -- Nolop, Keith -- Ibrahim, Prabha N -- Hirth, Peter -- Bollag, Gideon -- England -- Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466569" target="_blank"〉PubMed〈/a〉

Description: Antitumor immunity driven by intratumoral dendritic cells contributes to the efficacy of anthracycline-based chemotherapy in cancer. We identified a loss-of-function allele of the gene coding for formyl peptide receptor 1 (FPR1) that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1(-/-) mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Altogether, these results highlight the importance of FPR1 in chemotherapy-induced anticancer immune responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vacchelli, Erika -- Ma, Yuting -- Baracco, Elisa E -- Sistigu, Antonella -- Enot, David P -- Pietrocola, Federico -- Yang, Heng -- Adjemian, Sandy -- Chaba, Kariman -- Semeraro, Michaela -- Signore, Michele -- De Ninno, Adele -- Lucarini, Valeria -- Peschiaroli, Francesca -- Businaro, Luca -- Gerardino, Annamaria -- Manic, Gwenola -- Ulas, Thomas -- Gunther, Patrick -- Schultze, Joachim L -- Kepp, Oliver -- Stoll, Gautier -- Lefebvre, Celine -- Mulot, Claire -- Castoldi, Francesca -- Rusakiewicz, Sylvie -- Ladoire, Sylvain -- Apetoh, Lionel -- Bravo-San Pedro, Jose Manuel -- Lucattelli, Monica -- Delarasse, Cecile -- Boige, Valerie -- Ducreux, Michel -- Delaloge, Suzette -- Borg, Christophe -- Andre, Fabrice -- Schiavoni, Giovanna -- Vitale, Ilio -- Laurent-Puig, Pierre -- Mattei, Fabrizio -- Zitvogel, Laurence -- Kroemer, Guido -- New York, N.Y. -- Science. 2015 Nov 20;350(6263):972-8. doi: 10.1126/science.aad0779. Epub 2015 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. Universite Pierre et Marie Curie, Paris, France. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. Universite Pierre et Marie Curie, Paris, France. Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China. Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Faculte de Medecine, Universite Paris-Saclay, Kremlin-Bicetre, France. ; Regina Elena National Cancer Institute, Rome, Italy. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France. ; Department of Hematology, Oncology, and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy. ; Italian National Research Council, Institute for Photonics and Nanotechnology, Rome, Italy. ; Genomics and Immunoregulation, Life and Medical Science Center Institute, University of Bonn, Germany. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U981, Villejuif, France. ; Universite Paris Sorbonne Cite, UMRS 775, INSERM, Paris, France. INSERM U1147, Centre de Ressources Biologiques (CRB) EPIGENETIC, Paris, France. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Faculte de Medecine, Universite Paris-Saclay, Kremlin-Bicetre, France. Sotio, Prague, Czech Republic. ; Department of Medical Oncology, Centre Georges-Francois Leclerc, Dijon, France. Universite Bourgogne Franche-Comte, Dijon, France. Centre Georges Francois Leclerc, Dijon, France. ; Department of Life Sciences, University of Siena, Siena, Italy. ; Institut du Cerveau et de la Moelle Epiniere, ICM CNRS UMR 7225 - INSERM U 1127 - UPMC-P6 UMR S 1127, Equipe Neurogenetique et Physiologie Hopital de la Pitie-Salpetriere, 47, Boulevard de l'Hopital, 75013 Paris, France. ; INSERM U1147, Centre de Ressources Biologiques (CRB) EPIGENETIC, Paris, France. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif Cedex, France. ; Faculte de Medecine, Universite Paris-Saclay, Kremlin-Bicetre, France. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif Cedex, France. ; INSERM, U981, Villejuif, France. Department of Breast Oncology, Gustave Roussy Cancer Campus, Villejuif, France. ; University of Franche-Comte, INSERM 1098, France. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U981, Villejuif, France. Department of Biology and Pathology, Gustave Roussy Cancer Campus, Villejuif, France. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. ; Regina Elena National Cancer Institute, Rome, Italy. Department of Biology, University of Rome "Tor Vergata," Rome, Italy. ; Universite Paris Sorbonne Cite, UMRS 775, INSERM, Paris, France. INSERM U1147, Centre de Ressources Biologiques (CRB) EPIGENETIC, Paris, France. Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France. ; Gustave Roussy Cancer Campus, Villejuif, France. Faculte de Medecine, Universite Paris-Saclay, Kremlin-Bicetre, France. INSERM, U1015, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France. kroemer@orange.fr laurence.zitvogel@gustaveroussy.fr. ; Gustave Roussy Cancer Campus, Villejuif, France. INSERM, U1138, Paris, France. Equipe 11 Labellisee par la Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France. Universite Paris Descartes, Sorbonne Paris Cite, Paris, France. Universite Pierre et Marie Curie, Paris, France. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France. Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France. Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, 17176 Stockholm, Sweden. kroemer@orange.fr laurence.zitvogel@gustaveroussy.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26516201" target="_blank"〉PubMed〈/a〉

Description: Chiral amines are widely used as catalysts in asymmetric synthesis to activate carbonyl groups for α-functionalization. Carbonyl catalysis reverses that strategy by using a carbonyl group to activate a primary amine. Inspired by biological carbonyl catalysis, which is exemplified by reactions of pyridoxal-dependent enzymes, we developed an N-quaternized pyridoxal catalyst for the asymmetric Mannich reaction of glycinate with aryl N -diphenylphosphinyl imines. The catalyst exhibits high activity and stereoselectivity, likely enabled by enzyme-like cooperative bifunctional activation of the substrates. Our work demonstrates the catalytic utility of the pyridoxal moiety in asymmetric catalysis.

Description: We present a novel method to determine solar wind proxies from sheath measurements at Mars. Specifically, we develop an artificial neural network (ANN) to simultaneously infer seven solar wind proxies: ion density, ion speed, ion temperature, and interplanetary magnetic field magnitude and its vector components, using spacecraft measurements of ion moments, magnetic field magnitude, magnetic field components in the sheath, and the solar extreme ultraviolet flux. The ANN was trained and tested using3 years of data from the Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft. When compared with MAVEN spacecraft's in situ measured values of the solar wind parameters, we find that the ANN proxies for the solar wind ion density, ion speed, ion temperature, and interplanetary magnetic field magnitude havepercentage differences of 50% or less for 84.4%, 99.9%, 86.8%, and 79.8% of the instances, respectively. Forthe cone angle and clock angle proxies, 69.1% and 53.3% of instances, respectively, have angle differences of 30* or less.

Description: The identification of magnetic reconnection on the dayside of Mars has been elusive owing to the lack of comprehensive plasma and field measurements. Here we present direct measurements of dayside in situ reconnection signatures by the comprehensive particles and fields package on board the Mars Atmosphere and Volatile EvolutioN (MAVEN) spacecraft over strong crustal magnetic fields in the southern hemisphere of Mars. During a crossing of a bifurcated current sheet consisting of northward and southward magnetic fields, MAVEN recorded (i) ionospheric photoelectrons trapped on closed magneticfield lines, (ii) Hall magnetic fields and a nonzero normal field with polarity consistent with a crossing northward of the X line, and (iii) northward Alfvenic ion jets. Dayside magnetic reconnection on crustal magnetic fields could control the global configuration and topology of the Martian magnetosphere and alter the ion escape pattern from the dayside ionosphere.