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Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies.

Abstract Pancreatic ductal adenocarcinoma (PDA) patients have not yet benefitted from the revolution in cancer immunotherapy due in large part to the dominantly immunosuppressive tumor microenvironment (TME). MEK inhibition combined with autophagy inhibition leads to transient tumor responses in some PDA patients. We find that co-inhibition of MEK (using cobimetinib, COBI) and autophagy (using mefloquine, MFQ), but not either treatment alone, activates the Type I Interferon/STING pathway in tumor cells which in turn reprogram tumor associated macrophages (TAMs) in paracrine to foster an immunogenic switch. This effect is augmented by a CD40 agonist (aCD40). Triple therapy (COBI+MFQ+aCD40) achieved cytotoxic T cell activation in an immunologically “cold” mouse PDA model, leading to enhanced anti-tumor immunity. Collectively, MEK and autophagy co-inhibition coupled with CD40 agonism invokes immuno-reprograming and is an attractive therapeutic approach for PDA immunotherapy development. Competing Interest Statement The authors have declared no competing interest.

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci ( IQCK , ACE , ADAM10 , ADAMTS1 , and WWOX ), two of which ( ADAM10 , ACE ) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants ( P  = 1.32 × 10 −7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education. Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2 , ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease. We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants ( P < 1 × 10 −4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations ( P < 5 × 10 −8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 −10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 −10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 −14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Background A large number of longitudinal studies of population-based ageing cohorts are in progress internationally, but the insights from these studies into the risk and protective factors for cognitive ageing and conditions like mild cognitive impairment and dementia have been inconsistent. Some of the problems confounding this research can be reduced by harmonising and pooling data across studies. COSMIC (Cohort Studies of Memory in an International Consortium) aims to harmonise data from international cohort studies of cognitive ageing, in order to better understand the determinants of cognitive ageing and neurocognitive disorders. Methods/Design Longitudinal studies of cognitive ageing and dementia with at least 500 individuals aged 60 years or over are eligible and invited to be members of COSMIC. There are currently 17 member studies, from regions that include Asia, Australia, Europe, and North America. A Research Steering Committee has been established, two meetings of study leaders held, and a website developed. The initial attempts at harmonising key variables like neuropsychological test scores are in progress. Discussion The challenges of international consortia like COSMIC include efficient communication among members, extended use of resources, and data harmonisation. Successful harmonisation will facilitate projects investigating rates of cognitive decline, risk and protective factors for mild cognitive impairment, and biomarkers of mild cognitive impairment and dementia. Extended implications of COSMIC could include standardised ways of collecting and reporting data, and a rich cognitive ageing database being made available to other researchers. COSMIC could potentially transform our understanding of the epidemiology of cognitive ageing, and have a world-wide impact on promoting successful ageing.

Brian W. Kunkle®, Benjamin Grenier-Boley, Rebecca Sims, Joshua C. Bis, Vincent Damotte, Adam C. Naj, Anne Boland, Maria Vronskaya, Sven J. van der Lee©, Alexandre Amlie-Wolf©, Céline Bellenguez ), Aura Frizatti, Vincent Chouraki, Eden R. Martin, Kristel Sleegers©, Nandini Badarinarayan, Johanna Jakobsdottir, Kara L. Hamilton-Nelson, Sonia Moreno-Grau, Robert Olaso, Rachel Raybould, Yuning Chen®, Amanda B. Kuzma, Mikko Hiltunen, Taniesha Morgan, Shahzad Ahmad, Badri N. Vardarajan, Jacques Epelbaum, Per Hoffmann, Merce Boada, Gary W. Beecham, Jean-Guillaume Garnier, Denise Harold, Annette L. Fitzpatrick, Otto Valladares, Marie-Laure Moutet, Amy Gerrish, Albert V. Smith, Liming Qu, Delphine Bacq, Nicola Denning, Xueqiu Jian, Yi Zhao, Maria Del Zompo, Nick C. Fox, Seung-Hoan Choi, Ignacio Mateo, Joseph T. Hughes, Hieab H. Adams©, John Malamon, Florentino Sanchez-Garcia, Yogen Patel, Jennifer A. Brody©, Beth A. Dombroski, Maria Candida Deniz Naranjo, Makrina Daniilidou, Gudny Eiriksdottir, Shubhabrata Mukherjee, David Wallon, James Uphill, Thor Aspelund©, Laura B. Cantwell, Fabienne Garzia, Daniela Galimberti, Edith Hofer, Mariusz Butkiewicz, Bertrand Fin, Elio Scarpini, Chloe Sarnowski, Will S. Bush ), Stéphane Meslage, Johannes Kornhuber, Charles C. White, Yuenjoo Song, Robert C. Barber >, Sebastiaan Engelborghs, Sabrina Sordon, Dina Voijnovic, Perrie M. Adams, Rik Vandenberghe, Manuel Mayhaus, L. Adrienne Cupples©, Marilyn S. Albert, Peter P. De Deyn®, Wei Gu, Jayanadra J. Himali®, Duane Beekly, Alessio Squassina®, Annette M. Hartmann, Adelina Orellana, Deborah Blacker, Eloy Rodriguez-Rodriguez, Simon Lovestone, Melissa E. Garcia, Rachelle S. Doody, Carmen Munoz-Fernadez, Rebecca Sussams, Honghuang Lin®, Thomas J. Fairchild, Yolanda A. Benito, Clive Holmes, Hata Karamujić-Čomić, Matthew P. 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Burns, Michelangelo Mancuso®, Joseph D. Buxbaum, Ubaldo Bonuccelli, Nigel J. Cairns, Andrew McQuillin ), Chuanhai Cao, Gill Livingston, Chris S. Carlson, Nicholas J. Bass, Cynthia M. Carlsson, John Hardy, Regina M. Carney, Jose Bras, Minerva M. Carrasquillo, Rita Guerreiro, Mariet Allen, Helena C. Chui, Elizabeth Fisher D, Carlo Masullo, Elizabeth A. Crocco, Charles DeCarli, Gina Bisceglio, Malcolm Dick, Li Ma, Ranjan Duara, Neill R. Graff-Radford, Denis A. Evans, Angela Hodges, Kelley M. Faber, Martin Scherer, Kenneth B. Fallon, Matthias Riemenschneider, David W. Fardo®, Reinhard Heun, Martin R. Farlow, Heike Kölsch, Steven Ferris, Markus Leber, Tatiana M. Foroud, Isabella Heuser, Douglas R. Galasko, Ina Giegling, Marla Gearing, Michael Hüll, Daniel H. Geschwind, John R. Gilbert, John Morris, Robert C. Green, Kevin Mayo, John H. Growdon, Thomas Feulner, Ronald L. Hamilton®, Lindy E. Harrell, Dmitriy Drichel, Lawrence S. Honig, Thomas D. Cushion, Matthew J. 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Pericak-Vance ) Correction to: In the version of this article originally published, the name of author Gennady Roshchupkin was incorrectly spelled as Gena Roschupkin. The error has been corrected in the HTML and PDF versions of the article.