The Agent Institute: Develop an Infrastructure for Agent-Based Research and Development for the State of Maine

This award provides support to establish The Agent Institute (AI), an organization anticipated to become self-sustaining and generally enhance research and development for the State of Maine. The AI will promote interactions between industry and foster computer-technology research, specifically in software development and software-hardware relationships in the area of robotics. Industrial applications in extreme or hazardous environments will be emphasized because agent-based systems are designed to read/sense environmental information, make decisions, and take actions based on the information sensed and processed. The award provides an initial two years of salary support to hire an executive director and an administrative assistant. These individuals will be responsible for developing a series of workshops designed to bring researchers and developers with interests and expertise in agent-based systems together in collaborative projects. Education and outreach efforts will also be part of the AI\u27s mission to bring knowledge about this area to K-12 educators and schools with the goal of encouraging students toward careers in agent-based systems and high technology in general

Calcium Independent Effect of Orai1 and STIM1 in Non-Hodgkin B Cell Lymphoma Dissemination

International audienceCa 2+ release-activated Ca 2+ channels, composed of Orai1 and STIM1 (stromal interaction molecule 1) proteins, are the main Ca 2+ entry mechanism in lymphocytes. Their role in cell migration and metastasis is demonstrated in solid cancers but it remains elusive in malignant hemopathies. Diffuse large B cell lymphoma (DLBCL) is characterized by the dissemination of neoplastic B cells throughout the organism which is under the control of chemokines such as Stromal Derived Factor 1 (SDF-1) and its receptor CXCR4. CXCR4 activation triggers a complex intracellular signaling including an increase in intracellular Ca 2+ concentration whose role is still unclear. Using pharmacological and genetic approaches, we revealed that STIM1 and Orai1 were responsible for Ca 2+ influx induced by SDF-1. Furthermore, we provide in vitro and in vivo evidence that they are necessary for basal or SDF-1-induced DLBCL cell migration which is independent of Ca 2+ entry. We identify that they act as effectors coupling RhoA and ROCK dependent signaling pathway to MLC2 phosphorylation and actin polymerization. Finally, we revealed an alteration of Orai1 and STIM1 expression in extra-nodal DLBCL. Thus, we discovered a novel Ca 2+-independent but Orai1 and STIM1-dependent signaling pathway involved in basal and CXCR4 dependent cell migration, which could be relevant for DLBCL physiopathology

Wide-field optical spectroscopy system integrating reflectance and spatial frequency domain imaging to measure attenuation-corrected intrinsic tissue fluorescence in radical prostatectomy specimens

The development of a multimodal optical imaging system is presented that integrates endogenous fluorescence and diffuse reflectance spectroscopy with single-wavelength spatial frequency domain imaging (SFDI) and surface profilometry. The system images specimens at visible wavelengths with a spatial resolution of 70 microm, a field of view of 25 cm(2) and a depth of field of approximately 1.5 cm. The results of phantom experiments are presented demonstrating the system retrieves absorption and reduced scattering coefficient maps using SFDI with <6% reconstruction errors. A phase-shifting profilometry technique is implemented and the resulting 3-D surface used to compute a geometric correction ensuring optical properties reconstruction errors are maintained to <6% in curved media with height variations <20 mm. Combining SFDI-computed optical properties with data from diffuse reflectance spectra is shown to correct fluorescence using a model based on light transport in tissue theory. The system is used to image a human prostate, demonstrating its ability to distinguish prostatic tissue (anterior stroma, hyperplasia, peripheral zone) from extra-prostatic tissue (urethra, ejaculatory ducts, peri-prostatic tissue). These techniques could be integrated in robotic-assisted surgical systems to enhance information provided to surgeons and improve procedural accuracy by minimizing the risk of damage to extra-prostatic tissue during radical prostatectomy procedures and eventually detect residual cancer

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Programme de recherches interdisciplinaires « Vérité et fiction »

Stéphane Breton, Jean-Paul Colleyn, André Gunthert, Jean-Claude Penrad, Annick Bouleau, Sabine Chalvon, Daniel Dayan, Renaud Dulong, Éliane de Latour, Catarina Pasqualino, Dominique Pasquier, Marc-Henri Piault, Jean-Pierre Bertin-Maghit, Jacqueline Chervin, Emmannuel Grimaud, Roger Odin, Laurence Allard Allard, Gilles Saussier, Elodie Perreau Nous avons poursuivi nos travaux sur la tension (majeure), entre la vérité et la fiction dans les formes d’expression audiovisuelles. Roger Odin (Univer..

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

BACKGROUND: Activated phosphoinositide 3-kinase δ syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ). OBJECTIVE: We sought to review the clinical, immunologic, histopathologic, and radiologic features of APDS in a large genetically defined international cohort. METHODS: We applied a clinical questionnaire and performed review of medical notes, radiology, histopathology, and laboratory investigations of 53 patients with APDS. RESULTS: Recurrent sinopulmonary infections (98%) and nonneoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system; consistent with this, PI3Kδ is broadly expressed in the developing murine central nervous system. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60%). Increased IgM levels (78%), IgG deficiency (43%), and CD4 lymphopenia (84%) were significant immunologic features. No immunologic marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and 5 patients underwent hematopoietic stem cell transplantation. Five patients died from complications of APDS. CONCLUSION: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of hematopoietic stem cell transplantation for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.T.C. is supported by National Children’s Research Centre, Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland. A.C. has a Wellcome Trust Postdoctoral Training Fellowship for Clinicians (103413/Z/13/Z). K.O. is supported by funding from BBSRC, MRC, Wellcome Trust and GSK. R.D. and D.S.K are funded by National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK. C.S. and S.E. are supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803 grant to the Center of Chronic immunodeficiency and BMBF 01GM1111B grant to the PID-NET initiative). S.N.F is supported in part by the Southampton UK National Institute for Health Research (NIHR) Wellcome Trust Clinical Research Facility and NIHR Respiratory Biomedical Research Unit. M.A.A.I. is funded by NHS Innovation London and King’s College Hospital Charitable Trust. A.F., S.L., A.D., F.R-L and S.K. are supported by the European Union’s 7th RTD Framework Programme (ERC advanced grant PID-IMMUNE contract 249816) and a government grant managed by the French Agence Nationale de la Recherche as part of the "Investments for the Future" program (ANR-10-IAHU-01). S.L. is supported by the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01), the Foundation ARC pour la Recherche sur le Cancer (France), the Rare Diseases Foundation (France) and François Aupetit Association (France). S.L. is a senior scientist and S.K is a researcher at the Centre National de la Recherche Scientifique-CNRS (France). A.D. and S.K. are supported by the “Institut National de la Santé et de la Recherche Médicale". S.K. also supported by the Fondation pour la Recherche Médicale (grant number: ING20130526624), la Ligue Contre le Cancer (Comité de Paris) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH). S.O.B is supported by the Higher Education Funding Council for England. B.V. is supported by the UK Biotechnology and Biological Sciences Research Council [BB/I007806/1], Cancer Research UK [C23338/A15965) and the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre. B.V. is consultant to Karus Therapeutics (Oxford, UK). S.N. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science (095198/Z/10/Z). S.N. is also supported by the European Research Council Starting grant 260477, the EU FP7 collaborative grant 261441 (PEVNET project) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, UK. A.M.C. is funded by the Medical Research Council, British Lung Foundation, University of Sheffield and Cambridge NIHR-BRC. Research in A.M.C. laboratory has received non-commercial grant support from GSK, Novartis, and MedImmune.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.jaci.2016.06.02

Programme de recherches interdisciplinaires « Vérité et fiction »

Stéphane Breton, Jean-Paul Colleyn, André Gunthert, Jean-Claude Penrad, Annick Bouleau, Sabine Chalvon, Daniel Dayan, Renaud Dulong, Éliane de Latour, Catarina Pasqualino, Dominique Pasquier, Marc-Henri Piault, Jean-Pierre Bertin-Maghit, Jacqueline Chervin, Emmannuel Grimaud, Roger Odin, Laurence Allard Allard, Gilles Saussier, Elodie Perreau Nous avons poursuivi nos travaux sur la tension (majeure), entre la vérité et la fiction dans les formes d’expression audiovisuelles. Roger Odin (Univer..