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7. Improved Therapy Response Assessment in Metastatic Brain Tumors (TREATMENT)

Author

Hospital of Southern Norway Trust, Ostfold Hospital Trust, St. Olavs Hospital, Massachusetts General Hospital, Dana-Farber Cancer Institute, University Medical Center Groningen, University of Texas Southwestern Medical Center, South-Eastern Norway Regional Health Authority, Norwegian Cancer Society, and Kyrre Eeg Emblem, Principal Investigator

Published
2023

22. Prostate Cancer Risk in Firefighters

Author

Cancer Registry of Norway, Extrastiftelsen, National Institute of Occupational Health, Norwegian Confederation of Trade Unions, Fagforbundet, Gjensidige Foundation, Norwegian Cancer Society, Norwegian Firefighters Fight Cancer, Norwegian Labour Inspection Authority, and Jarle Jakobsen, PhD-student

Published
2020

23. Smoking Cessation in Cancer Treatment

Author

Norwegian Cancer Society, Helse Stavanger HF, Oslo University Hospital, Sorlandet Hospital HF, University Hospital of North Norway, Helse Møre og Romsdal HF, St. Olavs Hospital, and Arnfinn Helleve, Researcher

Published
2019

36. The phosphoinositide coincidence detector Phafin2 promotes macropinocytosis by coordinating actin organisation at forming macropinosomes

Author

Helene Spangenberg, Coen Campsteijn, Harald Stenmark, Jost Enninga, Kia Wee Tan, Marte Sneeggen, Domenica Martorana, Camilla Raiborg, Virginie Stévenin, Kay Oliver Schink, University of Oslo (UiO), Leiden University Medical Center (LUMC), Universiteit Leiden, Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and K.O.S was supported by a career development fellowship from the Norwegian Cancer Society, a Career grant from the South–Eastern Norway Regional Health Authority (2020038), and a Research Grant from the Research Council of Norway (315103). C.C. is a young investigator of the Research Council of Norway. H.S. was supported by an Open Project Grant from the South–Eastern Norway Regional Health Authority (2018081), a Research Grant from the Norwegian Cancer Society (182698), and an Advanced Grant from the European Research Council (788954). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 179571.

Subjects
Endosome, [SDV]Life Sciences [q-bio], Science, Vesicular Transport Proteins, General Physics and Astronomy, macromolecular substances, Endosomes, Endocytosis, Phosphatidylinositols, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Phosphatidylinositol Phosphates, Salmonella, Animals, Humans, Macropinosome, Actin, Multidisciplinary, Chemistry, Pinocytosis, Cell Membrane, Biological Transport, General Chemistry, Actin cytoskeleton, Actins, Cell biology, Pleckstrin homology domain, FYVE domain, Transcriptome
Abstract

Uptake of large volumes of extracellular fluid by actin-dependent macropinocytosis has an important role in infection, immunity and cancer development. A key question is how actin assembly and disassembly are coordinated around macropinosomes to allow them to form and subsequently pass through the dense actin network underlying the plasma membrane to move towards the cell center for maturation. Here we show that the PH and FYVE domain protein Phafin2 is recruited transiently to newly-formed macropinosomes by a mechanism that involves coincidence detection of PtdIns3P and PtdIns4P. Phafin2 also interacts with actin via its PH domain, and recruitment of Phafin2 coincides with actin reorganization around nascent macropinosomes. Moreover, forced relocalization of Phafin2 to the plasma membrane causes rearrangement of the subcortical actin cytoskeleton. Depletion of Phafin2 inhibits macropinosome internalization and maturation and prevents KRAS-transformed cancer cells from utilizing extracellular protein as an amino acid source. We conclude that Phafin2 promotes macropinocytosis by controlling timely delamination of actin from nascent macropinosomes for their navigation through the dense subcortical actin network., Macropinocytosis permits the cellular uptake of fluids and nutrients via macropinosomes. Here, the authors show that Phafin2 is required for the formation of macropinosomes and permits their transit through dense actin networks.

Published
2021

37. Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci

Author

Chen, Hongjie, Fan, Shaoqi, Stone, Jennifer, Thompson, Deborah J, Douglas, Julie, Li, Shuai, Scott, Christopher, Bolla, Manjeet K, Wang, Qin, Dennis, Joseph, Michailidou, Kyriaki, Li, Christopher, Peters, Ulrike, Hopper, John L, Southey, Melissa C, Nguyen-Dumont, Tu, Nguyen, Tuong L, Fasching, Peter A, Behrens, Annika, Cadby, Gemma, Murphy, Rachel A, Aronson, Kristan, Howell, Anthony, Astley, Susan, Couch, Fergus, Olson, Janet, Milne, Roger L, Giles, Graham G, Haiman, Christopher A, Maskarinec, Gertraud, Winham, Stacey, John, Esther M, Kurian, Allison, Eliassen, Heather, Andrulis, Irene, Evans, D Gareth, Newman, William G, Hall, Per, Czene, Kamila, Swerdlow, Anthony, Jones, Michael, Pollan, Marina, Fernandez-Navarro, Pablo, McConnell, Daniel S, Kristensen, Vessela N, NBCS Investigators, Rothstein, Joseph H, Wang, Pei, Habel, Laurel A, Sieh, Weiva, Dunning, Alison M, Pharoah, Paul, Easton, Douglas F, Gierach, Gretchen L, Tamimi, Rulla M, Vachon, Celine M, Lindström, Sara, Unión Europea. Comisión Europea. H2020, Canadian Institutes of Health Research, Quebec Breast Cancer Foundation, Government of Quebec (Canadá), National Institutes of Health (Estados Unidos), Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), Susan G. Komen Breast Cancer Foundation, Ovarian Cancer Research Foundation (Astrualia), Australian Breast Cancer Family Study, NIH - National Cancer Institute (NCI) (Estados Unidos), National Health and Medical Research Council (Australia), New South Wales Cancer Council (Reino Unido), Victorian Health Promotion Foundation, Victorian Cancer Agency, National Breast Cancer Foundation (Australia), Cancer Australia, Universitätsklinikum Erlangen (Alemania), Cancer Council Western Australia (Australia), Consorcio Gallego de Cáncer de Mama (BREOGAN), Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Galicia Sur Biomedical Foundation, Xunta de Galicia (España), Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Ministerio de Economía y Competitividad (España), Canadian Cancer Society, NIHR - Manchester Biomedical Research Center, Cancer Council Queensland (Australia), Cancer Council New South Wales (Australia), Cancer Council Victoria (Australia), Cancer Council Tasmania (Australia), Cancer Council South (Australia), United States Army Medical Research and Development Command, NIH - NCI-Specialized Programs of Research Excellence (SPORE) in Breast Cancer (Estados Unidos), The Research Council of Norway (Noruega), Southern and Eastern Norway Regional Health Authority (Noruega), Norwegian Cancer Society, Agency for Science, Technology and Research (Singapur), Institute of Cancer Research (Reino Unido), NIHR - Biomedical Research Centre (Reino Unido), Dennis, Joseph [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Lindström, Sara [0000-0002-7137-7281], and Apollo - University of Cambridge Repository

Subjects
Genome-wide association study (GWAS), Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, Breast Neoplasms, Polymorphism, Single Nucleotide, Breast cancer, Phenotype, Humans, Female, Genetic Predisposition to Disease, ddc:610, Transcriptome, Mammographic density, Research Article, Transcriptome-wide association study (TWAS), Breast Density, Genome-Wide Association Study
Abstract

Background: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. Methods: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. Results: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p

Published
2022
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38. Regulation of PRKN-independent mitophagy

Author

Ana Lapao, Petra Teresak, Patricia Boya, Zvulun Elazar, Nemanja Subic, Anne Simonsen, Israel Science Foundation, Sagol Institute for Longevity Research, Yeda-Sela Center for Basic Research (Israel), Research Council of Norway, Norwegian Cancer Society, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Tatiana Pérez de Guzmán el Bueno, Comunidad de Madrid, European Commission, Boya, Patricia [0000-0003-3045-951X], Elazar, Zvulun [0000-0002-3231-4464], Simonsen, Anne [0000-0003-4711-7057], Boya, Patricia, Elazar, Zvulun, and Simonsen, Anne

Subjects
0301 basic medicine, Autophagy receptors, Mitochondrial intermembrane space, Ubiquitin-Protein Ligases, Cellular homeostasis, PINK1, Review, mTORC1, Mitochondrion, Biology, Selective autophagy, 03 medical and health sciences, chemistry.chemical_compound, Mitophagy, Autophagy, Cardiolipin, Inner mitochondrial membrane, Molecular Biology, 030102 biochemistry & molecular biology, Cell Biology, Mitochondria, 3. Good health, Cell biology, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, chemistry, Mitochondrial Membranes, Mitochondrial dysfunction, Protein Kinases
Abstract

37 p.-3 fig.-1 tab., Mitochondria are dynamic, multifunctional cellular organelles that play a fundamental role in maintaining cellular homeostasis. Keeping the quality of mitochondria in check is of essential importance for functioning and survival of the cells. Selective autophagic clearance of flawed mitochondria, a process termed mitophagy, is one of the most prominent mechanisms through which cells maintain a healthy mitochondrial pool. The best-studied pathway through which mitophagy is exerted is the PINK1-PRKN pathway. However, an increasing number of studies have shown an existence of alternative pathways, where different proteins and lipids are able to recruit autophagic machinery independently of PINK1 and PRKN. The significance of PRKN-independent mitophagy pathways is reflected in various physiological and pathophysiological processes, but many questions regarding the regulation and the interplay between these pathways remain open. Here we review the current knowledge and recent progress made in the field of PRKN-independent mitophagy. Particularly we focus on the regulation of various receptors that participate in targeting impaired mitochondria to autophagosomes independently of PRKN., We are grateful for funding from the Israel Science Foundation (Grant #215/19), the Sagol Longevity Foundation, Joint NRF - ISF Research Fund (Grant #3221/19), and the Yeda-Sela Center for Basic Research, as well as the Research Council of Norway through its Centres of Excellence funding scheme (project number 262652 to AS) and FRIPRO (project number 221831 to AS) and the Norwegian Cancer Society (project number 171318 to AS). Research in PB lab is supported by (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) PGC2018-098557-B-I00 Neuroscience Projects from Fundación Tatiana Pérez de Guzmán el Bueno and 2017/BMD-3813 from Comunidad de Madrid. The first authors are supported by a Marie Skłodowska-Curie ETN grant under the European Union’s Horizon 2020 Research and Innovation Programme (Grant Agreement No 765912 DRIVE)

Published
2021

39. A CpG island hypermethylation profile of primary colorectal carcinomas and colon cancer cell lines

Author

Lind, Guro E, Thorstensen, Lin, Løvig, Tone, Meling, Gunn I, Hamelin, Richard, Rognum, Torleiv O, Esteller, Manel, Lothe, Ragnhild A, Department of Genetics, Norwegian Radium Hospital-Institute for Cancer Research, Institute of Forensic Medicine, University of Oslo (UiO)-National Hospital, Akershus University Hospital [Lørenskog], Instabilité des microsatellites et cancers [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Cancer Epigenetics Laboratory, Spanish National Cancer Research Center (CNIO), GEL is a Research Fellow and LT a Post-Doctoral Fellow of the Norwegian Cancer Society. TL is Post-Doctoral Fellow of the Norwegian Foundation for Health and Rehabilitation. The study was funded by grants from the Norwegian Cancer Society (A95068 and D97127 RAL)., Instabilité des microsatellites et cancers [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Maylin, Françoise

Subjects
Male, MGMT, MESH: Neoplasm Proteins, hMLH1, p16, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Cadherins, p14, MESH: DNA Methylation, Tumor Suppressor Protein p14ARF, TP53, colorectal carcinomas, Promoter Regions, Genetic, MESH: CpG Islands, E-cadherin, MESH: Genes, APC, Nuclear Proteins, MESH: Comparative Study, Cadherins, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, MESH: Nu, Neoplasm Proteins, MESH: Cyclin-Dependent Kinase Inhibitor p16, Colonic Neoplasms, CpG methylation, Female, Colorectal Neoplasms, MutL Protein Homolog 1, Genes, APC, MESH: Cell Line, Tumor, KRAS, MESH: Carrier Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, O(6)-Methylguanine-DNA Methyltransferase, Sex Factors, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, colon cancer cell lines, Humans, APC, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, MSI, Adaptor Proteins, Signal Transducing, MSS, MESH: Colonic Neoplasms, MESH: Humans, Research, DNA Methylation, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, digestive system diseases, MESH: Male, CpG Islands, MESH: Microsatellite Repeats, Carrier Proteins, MESH: Female, MESH: Colorectal Neoplasms, Microsatellite Repeats
Abstract

Background Tumor cell lines are commonly used as experimental tools in cancer research, but their relevance for the in vivo situation is debated. In a series of 11 microsatellite stable (MSS) and 9 microsatellite unstable (MSI) colon cancer cell lines and primary colon carcinomas (25 MSS and 28 MSI) with known ploidy stem line and APC, KRAS, and TP53 mutation status, we analyzed the promoter methylation of the following genes: hMLH1, MGMT, p16INK4a (CDKN2A α-transcript), p14ARF (CDKN2A β-transcript), APC, and E-cadherin (CDH1). We compared the DNA methylation profiles of the cell lines with those of the primary tumors. Finally, we examined if the epigenetic changes were associated with known genetic markers and/or clinicopathological variables. Results The cell lines and primary tumors generally showed similar overall distribution and frequencies of gene methylation. Among the cell lines, 15%, 50%, 75%, 65%, 20% and 15% showed promoter methylation for hMLH1, MGMT, p16INK4a, p14ARF, APC, and E-cadherin, respectively, whereas 21%, 40%, 32%, 38%, 32%, and 40% of the primary tumors were methylated for the same genes. hMLH1 and p14ARF were significantly more often methylated in MSI than in MSS primary tumors, whereas the remaining four genes showed similar methylation frequencies in the two groups. Methylation of p14ARF, which indirectly inactivates TP53, was seen more frequently in tumors with normal TP53 than in mutated samples, but the difference was not statistically significant. Methylation of p14ARF and p16INK4a was often present in the same primary tumors, but association to diploidy, MSI, right-sided location and female gender was only significant for p14ARF. E-cadherin was methylated in 14/34 tumors with altered APC further stimulating WNT signaling. Conclusions The present study shows that colon cancer cell lines are in general relevant in vitro models, comparable with the in vivo situation, as the cell lines display many of the same molecular alterations as do the primary carcinomas. The combined pattern of epigenetic and genetic aberrations in the primary carcinomas reveals associations between them as well as to clinicopathological variables, and may aid in the future molecular assisted classification of clinically distinct stages.

Published
2004

40. Nanoparticle-based biosensors for detection of extracellular vesicles in liquid biopsies

Author

Jesús M. de la Fuente, Alicia Llorente, María Moros, Alba Martín-Barreiro, Carlos Cuestas-Ayllon, Aija Line, Beatriz Martín-Gracia, Valeria Grazú, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Diputación General de Aragón, Research Council of Norway, Norwegian Cancer Society, South-Eastern Norway Regional Health Authority, CSIC - Unidad de Recursos de Información Científica para la Investigación (URICI), and Ministerio de Economía y Competitividad (España)

Subjects
0303 health sciences, Chemistry, Liquid Biopsy, Biomedical Engineering, Nanoparticle, Nanotechnology, Biosensing Techniques, 02 engineering and technology, General Chemistry, General Medicine, Extracellular vesicle, 021001 nanoscience & nanotechnology, Extracellular vesicles, Extracellular Vesicles, 03 medical and health sciences, Animals, Humans, Nanoparticles, General Materials Science, Cancer biomarkers, 0210 nano-technology, Biosensor, 030304 developmental biology
Abstract

Tumor-derived extracellular vesicles have emerged as an alternative source of cancer biomarkers in liquid biopsies. Despite their clinical potential, traditional methods for isolation and analysis have hampered their translation into the clinic. The use of nanomaterial-based biosensors can speed up the development of analytical methods for quantifying extracellular vesicles in a specific, highly reproducible, robust, fast and inexpensive way. Here we review the utility of extracellular vesicles as a novel type of liquid biopsies and the recent advances in nanoparticle-based biosensors for their analysis. We aim to emphasise the limitations and challenges that hinder extracellular vesicle analysis using these biosensors and point out potential solutions., This work was supported by the TRANSCAN2-JTC2016 call (Project PROSCANEXO), Spanish AEI funds (BIO2017-84246-C2-1-R project and Juan de la Cierva fellowship (IJCI-2016-30520) to M. M.) and Fondo Social de la DGA (grupos DGA). B. M. G. thanks the DGA Fellowship program for her PhD position. The Research Council of Norway, the Norwegian Cancer Society, and the South-Eastern Norway Regional Health Authority are also acknowledged., We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).

Published
2020

41. JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles

Author

Aziz Khan, Damir Baranasic, Benoit Ballester, Ieva Rauluseviciute, Fayrouz Hammal, Klaas Vandepoele, Paul Boddie, Anthony Mathelier, Daniel Schmelter, Rafael Riudavets-Puig, Wyeth W. Wasserman, Jérémy Lucas, François Parcy, Oriol Fornes, Boris Lenhard, Laura Turchi, Romain Blanc-Mathieu, Jaime A. Castro-Mondragon, Albin Sandelin, Nicolás Manosalva Pérez, Roza Berhanu Lemma, Tiffany Y. Leung, Alejandro Aguirre, Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Rigshospitalet [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, Régulateurs du développement de la fleur (Flo_RE ), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Stanford Cancer Institute - Stanford University School of Medicine, Department of Plant Biotechnology and Bioinformatics, Ghent University, VIBUGent Center for Plant Systems Biology, BC Children's Hospital Research Institute [Vancouver, BC, Canada] (BCCHR), University of British Columbia (UBC), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UCSC Genome Browser, University of California Santa Cruz, MRC London Institute of Medical Sciences (LMC), Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, The Bioinformatics Centre, Department of Biology & Biotech Research and Innovation Centre, University of Copenhagen, Department of Medical Genetics, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, NorwegianResearch Council [187615] and [288404], South-Eastern Norway Regional Health Authority (Helse Sør-Øst), Canadian Institutes of Health Research [PJT-162120], Natural Sciences andEngineeringResearch Council of Canada (NSERC) Discovery Grant [RGPIN-2017-06824], Norwegian Cancer Society [197884], NHGRI (National Human Genome Research Institute) [5U41HG002371-20], BOFgrant from Ghent University [BOF24Y2019001901], Novo Nordisk Foundation [NNF20OC0059951, NNF19OC0058262], Danish Cancer Foundation [R204A12359], Danish Independent Research Fund [611000207B, 7014-00120B], Carlsberg Foundation, ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), European Project: MSCA-ITN 2018,pHioniC, Universiteit Gent = Ghent University (UGENT), Imperial College London, University of Copenhagen = Københavns Universitet (UCPH), University of Oslo (UiO), Martin-Laffon, Jacqueline, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, and pH and Ion Transport in Pancreatic Cancer - pHioniC - MSCA-ITN 2018 - INCOMING

Subjects
AcademicSubjects/SCI00010, Genome browser, Biology, computer.software_genre, MOUSE, Genome, Bioconductor, Mice, 03 medical and health sciences, 0302 clinical medicine, ENRICHMENT ANALYSIS, Databases, Genetic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, Animals, Humans, Database Issue, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Taxonomic rank, MOTIF DATABASE, Transcription factor, TFBSSHAPE, 030304 developmental biology, TOOLS, 0303 health sciences, Binding Sites, Database, Computational Biology, Biology and Life Sciences, Genomics, Structural classification, Plants, GENE, DNA SHAPE-FEATURES, Vertebrates, computer, Software, 030217 neurology & neurosurgery, Protein Binding, Transcription Factors
Abstract

JASPAR (http://jaspar.genereg.net/) is an open-access database containing manually curated, non-redundant transcription factor (TF) binding profiles for TFs across six taxonomic groups. In this 9th release, we expanded the CORE collection with 341 new profiles (148 for plants, 101 for vertebrates, 85 for urochordates, and 7 for insects), which corresponds to a 19% expansion over the previous release. We added 298 new profiles to the Unvalidated collection when no orthogonal evidence was found in the literature. All the profiles were clustered to provide familial binding profiles for each taxonomic group. Moreover, we revised the structural classification of DNA binding domains to consider plant-specific TFs. This release introduces word clouds to represent the scientific knowledge associated with each TF. We updated the genome tracks of TFBSs predicted with JASPAR profiles in eight organisms; the human and mouse TFBS predictions can be visualized as native tracks in the UCSC Genome Browser. Finally, we provide a new tool to perform JASPAR TFBS enrichment analysis in user-provided genomic regions. All the data is accessible through the JASPAR website, its associated RESTful API, the R/Bioconductor data package, and a new Python package, pyJASPAR, that facilitates serverless access to the data.

Published
2021

42. Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage

Author

Martín-Alonso, Mara, Iqbal, Sharif, Vornewald, Pia M., Lindholm, Håvard T., Damen, Mirjam J., Martínez, Fernando, Hoel, Sigrid, Díez-Sánchez, Alberto, Altelaar, Maarten, Katajisto, Pekka, Arroyo, Alicia G., Oudhoff, Menno J., Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Norwegian University of Science and Technology, Central Norway Regional Health Authority, Norwegian Research Council, Norwegian Cancer Society, Martín-Alonso, Mara, Vornewald, Pia, Lindholm, Håvard Takle, Martínez, Fernando, Alberto Díez-Sánchez, Altelaar, Maarten, Katajisto, Pekka, Arroyo, Alicia G., Oudhoff, Menno, Afd Biomol.Mass Spect. and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Centre of Excellence in Stem Cell Metabolism, Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, Molecular and Integrative Biosciences Research Programme, Martín-Alonso, Mara [0000-0003-1624-3085], Vornewald, Pia [0000-0003-0810-1538], Lindholm, Håvard Takle [0000-0003-4403-4387], Martínez, Fernando [0000-0003-0908-9366], Alberto Díez-Sánchez [0000-0001-5146-3089], Altelaar, Maarten [0000-0001-5093-5945], Katajisto, Pekka [0000-0002-3033-4189], Arroyo, Alicia G. [0000-0002-1536-3846], and Oudhoff, Menno [000-0002-1180-8975]

Subjects
MATRIX METALLOPROTEINASES, Muscle, Smooth/metabolism, General Physics and Astronomy, Matrix metalloproteinase, Matrix Metalloproteinase 17/metabolism, ACTIVATION, 0302 clinical medicine, Intestinal Mucosa, Stem Cell Niche, 0303 health sciences, Multidisciplinary, Stem Cells/metabolism, Stem Cells, Matricellular protein, Intestinal stem cells, RNA sequencing, CANCER, 3. Good health, Cell biology, Intestines, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Muscle, Stem cell, medicine.symptom, Reprogramming, MESENCHYMAL CELLS, Signal Transduction, Regeneration/physiology, Science, Proteomic analysis, Inflammation, Biology, Periostin, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, COLON, medicine, PERIOSTIN, Regeneration, Animals, Humans, 030304 developmental biology, IDENTIFICATION, Smooth/metabolism, Signal Transduction/physiology, Regeneration (biology), Stem Cell Niche/physiology, Muscle, Smooth, General Chemistry, Matrix Metalloproteinase 17, Epithelium, 1182 Biochemistry, cell and molecular biology, Stem-cell niche, Intestinal Mucosa/metabolism, Intestines/cytology
Abstract

17 p.-8 fig., Smooth muscle is an essential component of the intestine, both to maintain its structure and produce peristaltic and segmentation movements. However, very little is known about other putative roles that smooth muscle cells may have. Here, we show that smooth muscle cells may be the dominant suppliers of BMP antagonists, which are niche factors essential for intestinal stem cell maintenance. Furthermore, muscle-derived factors render epithelium reparative and fetal-like, which includes heightened YAP activity. Mechanistically, we find that the membrane-bound matrix metalloproteinase MMP17, which is exclusively expressed by smooth muscle cells, is required for intestinal epithelial repair after inflammation- or irradiation-induced injury. Furthermore, we propose that MMP17 affects intestinal epithelial reprogramming after damage indirectly by cleaving diffusible factor(s) such as the matricellular protein PERIOSTIN. Together, we identify an important signaling axis that establishes a role for smooth muscle cells as modulators of intestinal epithelial regeneration and the intestinal stem cell niche., The WT KO crypt-muscle RNA-seq was done by the Genomics Core Facility at NTNU, which receives funding from the Faculty of Medicine and Health Sciences and Central Norway Regional Health Authority. This research was part of the Netherlands X-omics Initiative and partially funded by NWO (project 184.034.019). This work was further financially supported by the Norwegian Research Council (Centre of Excellence grant 223255/F50, and ‘Young Research Talent’ 274760 to M.J.O.) and the Norwegian Cancer Society (182767 to M.J.O.). MMA is the recipient of a Marie Skłodowska-Curie IF (DLV-794391).

Published
2021

43. Rab7b regulates dendritic cell migration by linking lysosomes to the actomyosin cytoskeleton

Author

Catharina Arnold-Schrauf, Nadia Mensali, Katharina Vestre, Cinzia Progida, Ana-Maria Lennon-Duménil, Oddmund Bakke, Noemi Antonella Guadagno, Irene Persiconi, Marine Bretou, Marc Dalod, Marita Borg Distefano, Sébastien Wälchli, University of Oslo (UiO), Department of Biology and Biotechnology 'Charles Darwin', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Oslo University Hospital [Oslo], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Norwegian Cancer Society, Norwegian Research Council, Southern and Eastern Norway Regional Health Authority (Helse Sor-Ost RHF), Anders Jahre Foundation (Anders Jahres Humanitaere Stiftelse), S. G. Sonneland Foundation,UNIFOR-FRIMED, (UNIFOR), Universitetet i Oslo, ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), European Project: 281225,EC:FP7:ERC,ERC-2011-StG_20101109,SYSTEMSDENDRITIC(2012), Caugant, Julien, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Harnessing systems immunology to unravel dendritic cell subset biology - SYSTEMSDENDRITIC - - EC:FP7:ERC2012-02-01 - 2017-01-31 - 281225 - VALID, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
0000-0003-4843-7626, M.D, O.B, C.P, Endosome, [SDV]Life Sciences [q-bio], Dendritic cells S.W, Endosomes, Rab7b, macromolecular substances, Biology, Microtubule Dynamics, 0000-0001-5869-1746, 03 medical and health sciences, Collective Cell Migration, Rab protein, Myosin, Humans, Cell migration, C.A.-S, 0000-0002-2477-337X, Cytoskeleton, Dendritic cell migration, Actin, 030304 developmental biology, 0303 health sciences, 0000-0002-9254-0690, 030302 biochemistry & molecular biology, Dendritic Cells, Actomyosin, Cell Biology, Cell biology, [SDV] Life Sciences [q-bio], RAB7B, 0000-0002-6436-7966, TFEB, Lysosomes, Research Article
Abstract

Lysosomal signaling facilitates the migration of immune cells by releasing Ca2+ to activate the actin-based motor myosin II at the cell rear. However, how the actomyosin cytoskeleton physically associates to lysosomes is unknown. We have previously identified myosin II as a direct interactor of Rab7b, a small GTPase that mediates the transport from late endosomes/lysosomes to the trans-Golgi network (TGN). Here, we show that Rab7b regulates the migration of dendritic cells (DCs) in one- and three-dimensional environments. DCs are immune sentinels that transport antigens from peripheral tissues to lymph nodes to activate T lymphocytes and initiate adaptive immune responses. We found that the lack of Rab7b reduces myosin II light chain phosphorylation and the activation of the transcription factor EB (TFEB), which controls lysosomal signaling and is required for fast DC migration. Furthermore, we demonstrate that Rab7b interacts with the lysosomal Ca2+ channel TRPML1 (also known as MCOLN1), enabling the local activation of myosin II at the cell rear. Taken together, our findings identify Rab7b as the missing physical link between lysosomes and the actomyosin cytoskeleton, allowing control of immune cell migration through lysosomal signaling. This article has an associated First Person interview with the first author of the paper., Summary: The small GTPase Rab7b bridges the lysosomal Ca2+ channel TRPML1 to myosin II, thus enabling the local activation of myosin II at the cell rear and promoting fast migration of dendritic cells.

Published
2021

44. Reference-based comparison of adaptive immune receptor repertoires

Author

Cédric R. Weber, Teresa Rubio, Longlong Wang, Wei Zhang, Philippe A. Robert, Rahmad Akbar, Igor Snapkov, Jinghua Wu, Marieke L. Kuijjer, Sonia Tarazona, Ana Conesa, Geir K. Sandve, Xiao Liu, Sai T. Reddy, Victor Greiff, Helmsley Charitable Trust, European Commission, Research Council of Norway, Norwegian Cancer Society, University of Oslo, Weber, Cédric R. [0000-0003-4802-8996], Rubio, Teresa [0000-0003-0707-9244], Wang, Longlong [0000-0002-6508-1804], Zhang, Wei [0000-0002-6968-6974], Robert, Philippe A. [0000-0003-1345-5015], Akbar, Rahmad [0000-0002-6692-0876], Snapkov, Igor [0000-0001-5341-685X], Kuijjer, Marieke L. [0000-0001-6280-3130], Tarazona, Sonia [0000-0001-5346-1407], Conesa, Ana [0000-0001-9597-311X], Sandve, Geir K. [0000-0002-4959-1409], Liu, Xiao [0000-0002-8073-0534], Reddy, Sai T. [0000-0002-9177-0857], Greiff, Victor [0000-0003-2622-5032], Weber, Cédric R., Rubio, Teresa, Wang, Longlong, Zhang, Wei, Robert, Philippe A., Akbar, Rahmad, Snapkov, Igor, Kuijjer, Marieke L., Tarazona, Sonia, Conesa, Ana, Sandve, Geir K., Liu, Xiao, Reddy, Sai T., and Greiff, Victor

Subjects
disease, animal diseases, ESTADISTICA E INVESTIGACION OPERATIVA, health, chemical and pharmacologic phenomena, biochemical phenomena, metabolism, and nutrition, Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, immune repertoire, computational immunology, Computer Science Applications, diagnostics, Genetics, bacteria, Radiology, Nuclear Medicine and imaging, Biotechnology
Abstract

B- and T-cell receptor (immune) repertoires can represent an individual’s immune history. While current repertoire analysis methods aim to discriminate between health and disease states, they are typically based on only a limited number of parameters (e.g., clonal diversity, germline usage). Here, we introduce immuneREF: a quantitative multi-dimensional measure of adaptive immune repertoire (and transcriptome) similarity that allows interpretation of immune repertoire variation by relying on both repertoire features and cross-referencing of simulated and experimental datasets. immuneREF is implemented in an R package and was validated based on detection sensitivity of immune repertoires with known similarities and dissimilarities. To quantify immune repertoire similarity landscapes across health and disease, we applied immuneREF to >2400 datasets from individuals with varying immune states (healthy, [autoimmune] disease and infection [Covid-19], immune cell population). Importantly we discovered, in contrast to the current paradigm, that blood-derived immune repertoires of healthy and diseased individuals are highly similar for certain immune states, suggesting that repertoire changes to immune perturbations are less pronounced than previously thought. In conclusion, immuneREF implements population-wide analysis of immune repertoire similarity and thus enables the study of the adaptive immune response across health and disease states., Support was provided from The Helmsley Charitable Trust (#2019PG-T1D011, to VG), UiO WorldLeading Research Community (to VG), UiO:LifeSciences Convergence Environment Immunolingo (to VG and GKS), EU Horizon 2020 iReceptorplus (#825821) (to VG), a Research Council of Norway FRIPRO project (#300740, to VG), a Research Council of Norway IKTPLUSS project (#311341, to VG and GKS), a Norwegian Cancer Society grant (#215817, to VG), and Stiftelsen Kristian Gerhard Jebsen (K.G. Jebsen Coeliac Disease Research Centre) (to GKS), Swiss National Science Foundation (Project 31003A to S.T.R), the Norwegian Research Council, Helse Sør-Øst, and the University of Oslo through the Centre for Molecular Medicine Norway (#187615 to MLK).

Published
2022

45. A Nextflow pipeline for T-cell receptor repertoire reconstruction and analysis from RNA sequencing data

Author

Teresa Rubio, Maria Chernigovskaya, Susanna Marquez, Cristina Marti, Paula Izquierdo-Altarejos, Amparo Urios, Carmina Montoliu, Vicente Felipo, Ana Conesa, Victor Greiff, Sonia Tarazona, Helmsley Charitable Trust, European Commission, Norwegian Research Council, Norwegian Cancer Society, Fundación Ramón Areces, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Generalitat Valenciana, and Centro de Investigación Príncipe Felipe (España)

Subjects
Immune repertoire analysis, Minimal Hepatic Encephalopathy, ESTADISTICA E INVESTIGACION OPERATIVA, CD4 isolation, T-cell receptor, RNA sequencing
Abstract

T-cell receptor (TCR) analysis is relevant for the study of immune system diseases. The expression of TCRs is usually measured with targeted sequencing approaches where TCR genes are selectively amplified. However, many non-targeted RNA-seq experiments also contain reads of TCR genes, which could be leveraged for TCR expression analysis while reducing sample requirements and costs. Moreover, a step-by-step pipeline for the processing of transcriptome RNA-seq reads to deliver immune repertoire data is missing, and these types of analyses are usually not included in RNA-seq studies of immunological conditions. This represents a missed opportunity for complementing them with the analysis of the immune repertoire., We present a Nextflow pipeline for T-cell receptor repertoire reconstruction and analysis from RNA sequencing data. We used a case study where TCR repertoire profiles were recovered from bulk RNA-seq of isolated CD4 T cells from control patients, cirrhotic patients without and with Minimal Hepatic Encephalopathy (MHE). MHE is a neuropsychiatric syndrome, mediated by peripheral inflammation, that may affect cirrhotic patients. After the recovery of 498-1,114 distinct TCR beta chains per patient, repertoire analysis of patients resulted in few public clones, high diversity and elevated within-repertoire sequence similarity, independently of immune status. Additionally, TCRs associated with celiac disease and inflammatory bowel disease were significantly overrepresented in MHE patient repertoires. The provided computational pipeline functions as a resource to facilitate TCR profiling from RNA-seq data boosting immunophenotype analyses of immunological diseases., We acknowledge generous support by The Leona M. and Harry B. Helmsley Charitable Trust (#2019PG-T1D011, to VG), UiO World-Leading Research Community (to VG), UiO:LifeScience Convergence Environment Immunolingo (to VG), EU Horizon 2020 iReceptorplus (#825821) (to VG), a Research Council of Norway FRIPRO project (#300740, to VG), a Research Council of Norway IKTPLUSS project (#311341, to VG), a Norwegian Cancer Society Grant (#215817, to VG). This work was also supported in part by Fundación Ramón Areces (to CM), the Ministerio de Ciencia e Innovación Spain (SAF2017-82917-R and PID2020-113388RB-I00 to VF; FIS PI18/00150 to CM), Consellería Educación Generalitat Valenciana (PROMETEOII/2018/051 to VF), Ministerio de Economía y Competitividad (BIO2015-71658-R to AC), Centro de Investigación Príncipe Felipe (Ayudas para proyectos de investigación intergrupos to TR) and co-funded with European Regional Development Funds (ERDF to VF, CM, AC).

Published
2022

46. Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort

Author

Broberg, Karin E., Kippler, Maria J., Veldink, Jan Herman, Van Den Berg, Leonard H., Middleton, Lefkos T., Travis, Ruth C., Bergmann, Manuela M., Mancini, Francesca Romana, Katzke, Verena Andrea, Agudo, Antonio T., Gómez, Jesús Humberto, Rodríguez-Barranco, Miguel A., Trichopoulou, Antonia D., Vermeulen, Roel C.H., Peters, Susan, Broberg, Karin, Gallo, Valentina, Levi, Michael, Kippler, Maria, Vineis, Paolo, Veldink, Jan, Berg, Leonard, Middleton, Lefkos, Travis, Ruth, Bergmann, Manuela, Palli, Domenico, Grioni, Sara, Tumino, Rosario, Elbaz, Alexis, Vlaar, Tim, Mancini, Francesca, Kühn, Tilman, Katzke, Verena, Agudo, Antonio, Goñi, Fernando, Gómez, Jesús‐humberto, Rodríguez‐barranco, Miguel, Merino, Susana, Barricarte, Aurelio, Trichopoulou, Antonia, Jenab, Mazda, Weiderpass, Elisabete, Vermeulen, Roel, Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), FOOD‐CT‐2005‐513943 Ministry of National Education and Religious Affairs Cancer Research UK, CRUK Wellcome Trust, WT German Cancer Research Center, DKFZ Department of Health, Australian Government Institut National de la Santé et de la Recherche Médicale, Inserm Kræftens Bekæmpelse, DCS Instituto de Salud Carlos III, ISCIII: C03/09 Stichting Diabetes Onderzoek Nederland British Heart Foundation, BHF Norges Forskningsråd QLK4CT199900927 Stroke Association European Commission, EC Deutsche Krebshilfe World Cancer Research Fund, WCRF Kreftforeningen, NCS Medical Research Council, MRC, The EPIC study is funded by a number of grants, however, no funding source had any role in the preparation of this article. The EPIC study was funded by the Europe against Cancer program of the European Commission (SANCO), Italian Association for Research on Cancer, and Italian National Research Council. In addition, the authors thank the following for their financial support: the Environmental Cancer Risk, Nutrition, and Individual Susceptibility Network of Excellence, operating within the European Union Sixth Framework Program, Priority 5: Food Quality and Safety (FOOD‐CT‐2005‐513943), European Community Fifth Framework Program (grant QLK4CT199900927), ISCIII, Red de Centros RCESP (C03/09), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, Danish Cancer Society, Health Research Fund of the Spanish Ministry of Health, Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia, and Navarra, Cancer Research UK, Medical Research Council, UK, Stroke Association, UK, British Heart Foundation, Department of Health, UK, Food Standards Agency, UK, Wellcome Trust, UK, Greek Ministry of Health, Greek Ministry of Education, Italian Association for Research on Cancer, Italian National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Swedish Cancer, Swedish Scientific Council, Regional Government of Skåne and Västerbotten, Sweden, Norwegian Cancer Society, Research Council of Norway, French League against Cancer, INSERM, Mutuelle Generale l'Education National, and IGR. The EPIC‐Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC‐UU_12015/1) and Cancer Research UK (C864/A14136)., and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
0301 basic medicine, Adult, Male, Risk, medicine.medical_specialty, Clinical Neurology, Gastroenterology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, LEAD-EXPOSURE, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Research Articles, POPULATION, Aged, Retrospective Studies, Science & Technology, Neurology & Neurosurgery, business.industry, Amyotrophic Lateral Sclerosis, Neurosciences, 1103 Clinical Sciences, Retrospective cohort study, Odds ratio, Environmental exposure, Environmental Exposure, Mercury, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, 030104 developmental biology, Neurology, Cohort, Population study, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurosciences & Neurology, Neurology (clinical), SMOKING, 1109 Neurosciences, business, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Research Article, Cohort study
Abstract

International audience; Objective: Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. Methods: A nested ALS case–control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma–mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. Results: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1–15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08–3.87) and lead (OR = 1.89, 95% CI = 0.97–3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27–0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. Interpretation: This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a–n/a.

Published
2021

47. Global blood gene expression profiles following a breast cancer diagnosis-Clinical follow-up in the NOWAC post-genome cohort

Author

Marit Holden, Eiliv Lund, Lars Holden, Jean-Christophe Thalabard, Karina Standahl Olsen, Lill-Tove Busund, The Arctic University of Norway [Tromsø, Norway] (UiT), Norwegian Computing Center (NR), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University Hospital of North Norway [Tromsø] (UNN), The Artic University of Norway[Tromso, Norway], Cancer Registry of Norway, Halfdan Jacobsen of frues legat, Norwegian Cancer Society, and European Project: 232997,EC:FP7:ERC,ERC-2008-AdG,TICE(2009)

Subjects
0301 basic medicine, Oncology, Physiology, [SDV]Life Sciences [q-bio], Cancer Treatment, Gene Expression, Disease, Metastasis, Cohort Studies, 0302 clinical medicine, Breast Tumors, Basic Cancer Research, Medicine and Health Sciences, Registries, Medical diagnosis, Multidisciplinary, Genomics, Middle Aged, Body Fluids, 3. Good health, Blood, 030220 oncology & carcinogenesis, Cohort, Medicine, Female, Anatomy, Research Article, Adult, medicine.medical_specialty, Science, Immunology, Breast Neoplasms, 03 medical and health sciences, Breast cancer, Diagnostic Medicine, Internal medicine, Breast Cancer, Genetics, Cancer Detection and Diagnosis, medicine, Humans, VDP::Medisinske Fag: 700, [INFO]Computer Science [cs], Aged, business.industry, Gene Expression Profiling, Cancers and Neoplasms, Biology and Life Sciences, Cancer, medicine.disease, Cancer registry, VDP::Medical disciplines: 700, 030104 developmental biology, Metastatic Tumors, Immune System, business, Follow-Up Studies, Blood sampling
Abstract

Objective This explorative study aimed to assess if there are any time-dependent blood gene expression changes during the first one to eight years after breast cancer diagnosis, which can be linked to the clinical outcome of the disease. Material and methods A random distribution of follow-up time from breast cancer diagnosis till blood sampling was obtained by a nested, matched case-control design in the Norwegian Women and Cancer Post-genome Cohort. From 2002–5, women were invited to donate blood samples, regardless of any cancer diagnosis. At end of the study period in 2015, any cancer diagnoses in the 50 000 participants were obtained via linkage to the Norwegian Cancer Registry. For each breast cancer patient (n = 415), an age- and storage time-matched control was drawn. The design gave a uniform, random length of follow-up time, independent of cancer stage. Differences in blood gene expression between breast cancer cases and controls were identified using the Bioconductor R-package limma, using a moving window in time, to handle the varying time elapsed from diagnosis to blood sample. Results The number of differentially expressed genes between cases and controls were close to 2,000 in the first year after diagnosis, but fell sharply the second year. During the next years, a transient second increase was observed, but only in women with metastatic disease who later died, both compared to invasive cases that survived (p Conclusion This explorative analysis identified changing trajectories in the years after diagnosis, depending on clinical stage. Hypothetically, this could represent the escape of the metastatic cancer from the immune system.

Published
2021

48. Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

Author

Jean-Christophe Amé, Kathline Martin-Hernandez, Nicolas Kunath, José-Manuel Rodriguez-Vargas, Magnar Bjørås, Jing Ye, Wei Wang, F. Javier Oliver, Françoise Dantzer, Rajikala Suganthan, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), European Commission, Fundación Ramón Areces, Centre National de la Recherche Scientifique (France), Université de Strasbourg, France Génomique, Research Council of Norway, and Norwegian Cancer Society

Subjects
Cancer Research, Neurogenesis, Poly ADP ribose polymerase, Immunology, Aucun, Stem-cell differentiation, Mechanistic Target of Rapamycin Complex 2, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, mTORC2, Article, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Ubiquitin, medicine, Animals, lcsh:QH573-671, Progenitor cell, Mitosis, 030304 developmental biology, Mice, Knockout, 0303 health sciences, biology, lcsh:Cytology, Chemistry, NOX4, Cell Differentiation, Cell Biology, 3. Good health, Cell biology, Gene Expression Regulation, NADPH Oxidase 4, Astrocytes, biology.protein, Poly(ADP-ribose) Polymerases, Reactive Oxygen Species, 030217 neurology & neurosurgery, Oxidative stress, Signal Transduction, Neuroscience
Abstract

Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia., This work was funded by USIAS-2017-029 fellowship (to F.D) and RamonAreces Foundation (to J-M.R). The lab of F.D. is supported by Strasbourg University, Centre National de la recherche Scientifique and the LABEX ANR-10-LABX-0034_Medalis. Sequencing was performed by the Genom East platform, a member of the“France Génomique”consortium (ANR-10-INSB-0009). The labof M.B is supported by Health Authorities of Norway, Cancer Society of Norway, Research Council of Norway.

Published
2020

49. JASPAR 2020: update of the open-access database of transcription factor binding profiles

Author

Albin Sandelin, Solenne Correard, Xi Zhang, Aziz Khan, Boris Lenhard, Oriol Fornes, Ge Tan, Robin van der Lee, François Parcy, Phillip A. Richmond, Anthony Mathelier, Benoit Ballester, Bhavi P. Modi, Wyeth W. Wasserman, Jaime A. Castro-Mondragon, Walter Santana-Garcia, Jeanne Chèneby, Marius Gheorghe, Damir Baranasic, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute and Department of Medical Genetics, University of British Columbia (UBC), Centre for Molecular Medicine Norway (NCMM), Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Rigshospitalet [Copenhagen], Computational Regulatory Genomics, Imperial College London, Institute of Clinical Sciences, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Functional Genomics Center Zurich, University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulateurs du développement de la fleur (Flo_RE), Physiologie cellulaire et végétale (LPCV), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biotech Research and Innovation Centre (BRIC), University of Copenhagen = Københavns Universitet (KU), Sars International Center for Marine Molecular Biology, Oslo University Hospital Radiumhospitalet, NorwegianResearch Council [187615] [288404], Helse Sør-Øst, University of Oslo through the Centre for Molecular Medicine Norway, The Norwegian Cancer Society [197884], Canadian Institutes of Health [BOP-149430 and PJT-162120], Genome Canada and Genome British Columbia [255ONT and 275SIL], Michael Smith Foundation for Health Research [17746], Natural Sciences and Engineering Research Council of Canada Discovery Grant [RGPIN-2017-06824], CREATE programs, Weston Brain Institute [20R74681], BC Children’s Hospital Foundation and Research Institute, Netherlands Organization for Scientific Research [Rubicon fellow-ship, 452172015], Genome British Columbia [SIP007], Grants from the Lundbeck Foundation, the DanishCancer Foundation, the Danish Innovation Fund and the Danish Council forIndependent Research, ANR-16-CE92-0023,FLOPINET,Floral Pioneer Factors, ANR-10- LABX-49-01,Labex GRAL,Labex GRAL, Copenhagen University Hospital-Copenhagen University Hospital, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Régulateurs du développement de la fleur (Flo_RE ), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), ANR-16-CE92-0023,FLOPINET,Floral Pioneer Factors(2016), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Institut de biologie de l'ENS Paris (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), University of Copenhagen = Københavns Universitet (UCPH), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Biology, Web Browser, computer.software_genre, Bioconductor, 03 medical and health sciences, User-Computer Interface, 0302 clinical medicine, Databases, Genetic, Genetics, Animals, Database Issue, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Taxonomic rank, 030304 developmental biology, 0303 health sciences, Web browser, Binding Sites, Database, Computational Biology, Genomics, Multiple species, 3. Good health, 030220 oncology & carcinogenesis, computer, Software, Protein Binding, Transcription Factors
Abstract

JASPAR (http://jaspar.genereg.net) is an open-access database of curated, non-redundant transcription factor (TF)-binding profiles stored as position frequency matrices (PFMs) for TFs across multiple species in six taxonomic groups. In this 8th release of JASPAR, the CORE collection has been expanded with 245 new PFMs (169 for vertebrates, 42 for plants, 17 for nematodes, 10 for insects, and 7 for fungi), and 156 PFMs were updated (125 for vertebrates, 28 for plants and 3 for insects). These new profiles represent an 18% expansion compared to the previous release. JASPAR 2020 comes with a novel collection of unvalidated TF-binding profiles for which our curators did not find orthogonal supporting evidence in the literature. This collection has a dedicated web form to engage the community in the curation of unvalidated TF-binding profiles. Moreover, we created a Q&A forum to ease the communication between the user community and JASPAR curators. Finally, we updated the genomic tracks, inference tool, and TF-binding profile similarity clusters. All the data is available through the JASPAR website, its associated RESTful API, and through the JASPAR2020 R/Bioconductor package.

Published
2020

50. Physical activity patterns and the risk of colorectal cancer in the Norwegian Women and Cancer study: a population-based prospective study

Author

Kristin Benjaminsen Borch, Idlir Licaj, Sunday Oluwafemi Oyeyemi, Eiliv Lund, Tonje Braaten, The Arctic University of Norway (UiT), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), The cost of publishing this manuscript was paid by the Publication Fund ofUiT-The Arctic University of Norway. SOO, TB, IL, EL, and KBB were supportedby the Faculty of Health, UiT-The Arctic University of Norway. IL was supportedby the Norwegian Cancer Society., CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Duchange, Nathalie, The Arctic University of Norway [Tromsø, Norway] (UiT), and Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Cancer Research, medicine.medical_specialty, Colorectal cancer, Rectum, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Internal medicine, Surveys and Questionnaires, Genetics, medicine, Humans, Women, 030212 general & internal medicine, Prospective Studies, Registries, Rectal cancer, Prospective cohort study, Exercise, business.industry, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, Physical activity, Hazard ratio, Cancer, Middle Aged, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Confidence interval, 3. Good health, Cancer registry, Colon cancer, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, NOWAC, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Population Surveillance, Cohort, Female, business, Colorectal Neoplasms, Research Article
Abstract

Source at https://doi.org/10.1186/s12885-018-5092-0. Introduction: Colorectal cancer (CRC) remains the second most common cancer in women worldwide. Physical activity (PA) has been associated with reduced risk of CRC; however, this has been demonstrated more consistently in men, while results of studies in women have been largely equivocal. We aimed to further examine the relationship between PA patterns and the risk of CRC in women, using repeated measurements. Methods: We followed participants of the Norwegian Women and Cancer (NOWAC) Study - a nationally representative cohort. Baseline information was available for 79,184 women, and we used this information in addition to follow-up information collected 6–8 years later, for repeated measurement analysis. At enrollment, participants were cancer-free and aged 30–70 years, with a median age of 51 years. We used Cox proportional hazards regression to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During an average of 14.6 years of follow-up and 1.16 million person-years, 885 cases of colon and 426 cases of rectal cancer were identified through linkage to the Norwegian Cancer Registry (median age at diagnosis: 65 years). We found no association between PA level and the risk of colon cancer in baseline or repeated measurements analyses when comparing women with PA level 1–2 to those with PA level 5–6 (reference) (baseline: HR = 0.90, 95% CI 0.66–1.23, p-trend = 0.76; repeated measurements: HR = 0.78, 95% CI 0.55–1.10, p-trend = 0.27). Results were the same when comparing PA level 9–10 to the reference level (baseline: HR = 0.80, 95% CI 0.56–1.12, p-trend = 0.76; repeated measurements: HR = 0.82, 95% CI 0.58–1.16, p-trend = 0.27). Similarly, we found no association between PA levels and the risk of rectal cancer. Conclusions: Women may need to look beyond PA in order to reduce their risk of CRC.

Published
2018

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