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56 results on '"Cancerfonden"'

1. Reconstructing Schoolyards With Greenery to Increase Schoolchildren's Physical Activity and Mitigate Climate Changes

Author: The City of Stockholm, Cancerfonden, Arwidssonstiftelsen, and Daniel Berglind, Associate Professor
Published: 2024

2. ProBio: A Biomarker Driven Study in Patients With Metastatic Prostate Cancer (ProBio)

Author: The Swedish Research Council, Kom Op Tegen Kanker, Janssen Pharmaceutica N.V., Belgium, AstraZeneca, Cancerfonden, and Henrik Grönberg, Professor of Cancer Epidemiology
Published: 2024

3. Do Ionic Liquids Exhibit the Required Characteristics to Dissolve, Extract, Stabilize, and Purify Proteins? Past-Present-Future Assessment

Author: Universidade de Aveiro, European Commission, La Caixa, Knut and Alice Wallenberg Foundation, Swedish Research Council, Cancerfonden, Science and Engineering Research Board (India), Agencia Estatal de Investigación (España), Bharmoria, Pankaj [0000-0001-6573-0475], Tietze, Alesia A [0000-0002-9281-548X], Mondal, Dibyendu [0000-0002-1715-5514], Kang, Tejwant Singh [0000-0002-4589-9772], Kumar, Arvind [0000-0001-9236-532X], Freire, Mara G [0000-0001-8895-0614], Bharmoria, Pankaj, Tietze, Alesia A, Mondal, Dibyendu, Kang, Tejwant Singh, Kumar, Arvind, Freire, Mara G, Universidade de Aveiro, European Commission, La Caixa, Knut and Alice Wallenberg Foundation, Swedish Research Council, Cancerfonden, Science and Engineering Research Board (India), Agencia Estatal de Investigación (España), Bharmoria, Pankaj [0000-0001-6573-0475], Tietze, Alesia A [0000-0002-9281-548X], Mondal, Dibyendu [0000-0002-1715-5514], Kang, Tejwant Singh [0000-0002-4589-9772], Kumar, Arvind [0000-0001-9236-532X], Freire, Mara G [0000-0001-8895-0614], Bharmoria, Pankaj, Tietze, Alesia A, Mondal, Dibyendu, Kang, Tejwant Singh, Kumar, Arvind, and Freire, Mara G
Abstract: Proteins are highly labile molecules, thus requiring the presence of appropriate solvents and excipients in their liquid milieu to keep their stability and biological activity. In this field, ionic liquids (ILs) have gained momentum in the past years, with a relevant number of works reporting their successful use to dissolve, stabilize, extract, and purify proteins. Different approaches in protein-IL systems have been reported, namely, proteins dissolved in (i) neat ILs, (ii) ILs as co-solvents, (iii) ILs as adjuvants, (iv) ILs as surfactants, (v) ILs as phase-forming components of aqueous biphasic systems, and (vi) IL-polymer-protein/peptide conjugates. Herein, we critically analyze the works published to date and provide a comprehensive understanding of the IL-protein interactions affecting the stability, conformational alteration, unfolding, misfolding, and refolding of proteins while providing directions for future studies in view of imminent applications. Overall, it has been found that the stability or purification of proteins by ILs is bispecific and depends on the structure of both the IL and the protein. The most promising IL-protein systems are identified, which is valuable when foreseeing market applications of ILs, e.g., in "protein packaging" and "detergent applications". Future directions and other possibilities of IL-protein systems in light-harvesting and biotechnology/biomedical applications are discussed.
Published: 2024

4. Sodium Selenite as a Cytotoxic Agent in Advanced Carcinoma (SECAR)

Author: Cancerfonden, Cancer and Allergy Foundation, Cancerföreningen i Stockholm, Region Stockholm, and Ola Brodin, MD, PhD, Ass Prof, Senior consultant
Published: 2013

5. CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway

Author: Universidad de Sevilla. Departamento de Genética, Danish Cancer Society. Demmark, Lundbeck Foundation, Danish Council for Independent Research. Demmark, Novo Nordisk Foundation, Swedish Research Council, Swedish Cancer Foundation/Cancerfonden. Sweden, Danish National Research Foundation, Gómez Cabello, Daniel, Pappas, George, Aguilar Morante, Diana, Dinant, Christoffel, Bartek, Jiri, Universidad de Sevilla. Departamento de Genética, Danish Cancer Society. Demmark, Lundbeck Foundation, Danish Council for Independent Research. Demmark, Novo Nordisk Foundation, Swedish Research Council, Swedish Cancer Foundation/Cancerfonden. Sweden, Danish National Research Foundation, Gómez Cabello, Daniel, Pappas, George, Aguilar Morante, Diana, Dinant, Christoffel, and Bartek, Jiri
Abstract: The RNA world is changing our views about sensing and resolution of DNA damage. Here, we develop single-molecule DNA/RNA analysis approaches to visualize how nascent RNA facilitates the repair of DNA double-strand breaks (DSBs). RNA polymerase II (RNAPII) is crucial for DSB resolution in human cells. DSB-flanking, RNAPII-generated nascent RNA forms RNA:DNA hybrids, guiding the upstream DNA repair steps towards favouring the error-free Homologous Recombination (HR) pathway over Non-Homologous End Joining. Specific RNAPII inhibitor, THZ1, impairs recruitment of essential HR proteins to DSBs, implicating nascent RNA in DNA end resection, initiation and execution of HR repair. We further propose that resection factor CtIP interacts with and helps re-activate RNAPII when paused by the RNA:DNA hybrids, collectively promoting faithful repair of chromosome breaks to maintain genomic integrity.
Published: 2022

6. Causal effects of lifetime smoking on breast and colorectal cancer risk:Mendelian randomization study

Author: Marc J. Gunter, Inger T. Gram, Elisabete Weiderpass, Hilary A. Tindle, Sun-Seog Kweon, Renée T. Fortner, Rudolf Kaaks, Sarah J Lewis, James Yarmolinsky, Stephen B. Gruber, Marije F. Bakker, Li Hsu, Yi Lin, Neil Murphy, Polly A. Newcomb, Konstantinos K. Tsilidis, Noralane M. Lindor, Rosario Tumino, Gianluca Severi, Hermann Brenner, Emmanouil Bouras, Jane C. Figueiredo, Niki Dimou, Richard M. Martin, Bethany Van Guelpen, María-José Sánchez-Pérez, 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), 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, Cancerfonden Cancer Research Foundation in Northern Sweden Deutsche Krebshilfe Vetenskapsrådet, VR Australian Lions Childhood Cancer Research Foundation, ALCCRF Knut och Alice Wallenbergs Stiftelse State of Maryland Vetenskapsrådet, VR: VR 2017-00650 Centers for Disease Control and Prevention, CDC Institut National Du Cancer, INCa National Institutes of Health, NIH National Cancer Institute, NCI: P30 CA015704 Centre Hospitalier Universitaire de Nantes, CHU de Nantes Conseil Régional des Pays de la Loire Association Anne de Bretagne Genetique Centre Hospitalier Universitaire de Nantes, CHU de Nantes U.S. Public Health Service, USPHS: HHSN261201500005C U.S. Department of Health and Human Services, HHS National Institutes of Health, NIH National Cancer Institute, NCI National Institute on Aging, NIA: U01 AG18033 Institut National Du Cancer, INCa: P30 CA006973, U01 CA86308 American Institute for Cancer Research, AICR European Commission, EC National Institutes of Health, NIH: R01 CA189184, 2P30CA015704-40, R01 CA207371, U01 CA206110 Matthias Lackas-Stiftung Johns Hopkins University, JHU: HHSN268201200008I National Cancer Institute, NCI National Institutes of Health, NIH: R01 CA143247, R01 CA81488, U01 CA122839, U19 CA148107, U01 CA167551 National Institutes of Health, NIH National Institute of Environmental Health Sciences, NIEHS: T32 ES013678 National Cancer Institute, NCI U.S. Department of Health and Human Services, HHS: R01 CA197350, R01 CA81488, R01 CA201407, P01 CA196569, U19 CA148107, P30 CA014089 Österreichische Forschungsförderungsgesellschaft, FFG: 829675 Instituto de Salud Carlos III, ISCIII European Regional Development Fund, ERDF: PI14-613, PI09-1286 Xarxa de Bancs de Tumors de Catalunya, XBTC: PT13/0010/0013 Generalitat de Catalunya: 2017SGR723 Junta de Castilla y León: LE22A10-2 Agència de Gestió d'Ajuts Universitaris i de Recerca, AGAUR Ministerstvo Zdravotnictví Ceské Republiky, MZCR: AZV 17-30920A, AZV 15-27580A Grantová Agentura České Republiky, GA ČR: CZ GA CR: GAP304/10/1286, 1585 Deutsche Forschungsgemeinschaft, DFG: HO 5117/2-1, BR 1704/6-1, KL 2354/3-1, BR 1704/6-4, BR 1704/6-3, CH 117/1-1, HE 5998/2-1, RO 2270/8-1, BR1704/17-1 Bundesministerium für Bildung und Forschung, BMBF: 01ER0814, 01KH0404, 01ER0815, 01ER1505A, 01ER1505B U01 CA 84968-06 National Cancer Institute, NCI University of Maryland School of Public Health, SPH NIHR Imperial Biomedical Research Centre, BRC Imperial College London NIHR Imperial Biomedical Research Centre, BRC Centre International de Recherche sur le Cancer, CIRC Ministerie van Volksgezondheid, Welzijn en Sport, VWS Deutsche Krebshilfe Cancer Research UK, CRUK: C8221/A29017 Ministerie van Volksgezondheid, Welzijn en Sport, VWS Vetenskapsrådet, VR Ligue Contre le Cancer Bundesministerium für Bildung und Forschung, BMBF Bundesministerium für Bildung und Forschung, BMBF Kræftens Bekæmpelse, DCS Associazione Italiana per la Ricerca sul Cancro, AIRC Instituto de Salud Carlos III, ISCIII Deutsches Krebsforschungszentrum, DKFZ Institut National de la Santé et de la Recherche Médicale, Inserm National Research Council, NRC Institut Gustave-Roussy Deutsches Krebsforschungszentrum, DKFZ Cancerfonden World Cancer Research Fund, WCRF Medical Research Council, MRC: MR/M012190/1 Generalitat de Catalunya: 2017SGR653, 2014SGR135, 2014SGR255, 2017SGR21 SAF2014-54453R, SAF07-64873, SAF 2010-19273 Xunta de Galicia: PGIDIT07PXIB9101209PR Instituto de Salud Carlos III, ISCIII European Regional Development Fund, ERDF: PS09/02368, PI14/00230, 17/00878, PI08/1276, PI17/00509, PI08/0024, PI11/00681, P111/00219, PI14/00173 Xarxa de Bancs de Tumors de Catalunya, XBTC: SLT002/ 16/00398 GCB13131592CAST European Cooperation in Science and Technology, COST: CA17118, BM1206 Deutsche Krebshilfe National Institutes of Health, NIH: K07 CA190673, P01 CA055075, K07CA190673, R35CA197735, U01 CA167552, UM1 CA167552, R01 CA042182, P01 CA087969, R01 CA151993, P50 CA127003, UM1 CA186107, R35 CA197735, R01 CA137178 HCRI15011-1 National Cancer Institute, NCI: R01CA136726 Damon Runyon Cancer Research Foundation, DRCRF: CI-8 Food Standards Agency, FSA Cancer Research UK, CRUK: C588/A19167 VicHealth Cancer Council Victoria National Health and Medical Research Council, NHMRC: 251553, 209057, 509348, 504711 National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS: R01 CA81488 Florida Department of Health: 09BN-13 National Institutes of Health, NIH: R01 CA189184, P30 CA076292 National Institutes of Health, NIH: P30 DK034987, R01 CA66635 18226, 18223 Canadian Institutes of Health Research, CIHR: CRT 43821 National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS: U01 CA74783 Cancerfonden Cancer Research Foundation, CRF Vetenskapsrådet, VR Australian Lions Childhood Cancer Research Foundation, ALCCRF Canadian Cancer Society National Institutes of Health, NIH: U01/ U24 CA074783, U01 CA167551 Pelotonia CA16058, CA67941 Canadian Institutes of Health Research, CIHR: 112746 Ontario Research Foundation, ORF: GL201-043 National Cancer Institute, NCI U.S. Department of Health and Human Services, HHS: U01 HG004446, GEI U01 HG 004438, Z01 CP 010200 Division of Cancer Epidemiology and Genetics, National Cancer Institute, DCEG Institut National Du Cancer, INCa National Institutes of Health, NIH Division of Cancer Prevention, National Cancer Institute, DCP, NCI National Institutes of Health, NIH: U24 CA074794, U01 CA074794, R01 CA076366, U01 CA167551 National Cancer Institute, NCI National Institutes of Health, NIH: UM1 CA182883, U10 CA37429 National Cancer Institute, NCI Institut National Du Cancer, INCa: R03 CA153323, P01 CA074184, K05 CA152715, R01 CA097325 National Institutes of Health, NIH: KL2 TR000421 National Center for Advancing Translational Sciences, NCATS Stockholms Läns Landsting Vetenskapsrådet, VR: K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2 Karolinska Institutet, KI National Institutes of Health, NIH: K05 CA154337 Swedish Cancer Foundation National Heart, Lung, and Blood Institute, NHLBI National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS: HHSN268201100004C, HHSN268201100003C, HHSN268201100001C, HHSN271201100004C, HHSN268201100046C, HHSN268201100002C, R.M. Martin reports grants from Cancer Research UK during the conduct of the study. R.T. Fortner reports that grants from German Cancer Aid and from German Ministry of Education and Research supported the conduct of EPIC Heidelberg. S.B. Gruber reports other from Brogent International LLC outside the submitted work. B. van Guelpen reports grants from Swedish Research Council, Swedish Cancer Society, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation at Umea° University, and Cancer Research Foundation in Northern Sweden during the conduct of the study. No disclosures were reported by the other authors., CLUE: We appreciate the continued efforts of the staff members at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE II study. We thank the participants in CLUE. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/cancer, 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data., CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program., NSHDS investigators thank the Biobank Research Unit at Umea° University, the V€asterbotten Intervention Programme, the Northern Sweden MONICA study and Region V€asterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650)., Cancer incidence data have been provided by the District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Pennsylvania Cancer Registry, Texas Cancer Registry, Virginia Cancer Registry, and Wisconsin Cancer Reporting System. All are supported in part by funds from the Center for Disease Control and Prevention, National Program for Central Registries, local states or by the National Cancer Institute, Surveillance, Epidemiology, and End Results program. The results reported here and the conclusions derived are the sole responsibility of the authors., Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, R01CA201407). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704., ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des EntreprisesFranc¸aises dans la Luttecontre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue RégionaleContre le Cancer (LRCC)., The ATBC Study is supported by the Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health, and by U.S. Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services., CLUE funding was from the National Cancer Institute (U01 CA86308, Early Detection Research Network, and P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. COLO2&3: NIH (R01 CA60987).
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, medicine.drug_class, Colorectal cancer, Breast Neoplasms, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, Mendelian randomization, Genetic predisposition, Humans, Medicine, Risk factor, 11 Medical and Health Sciences, business.industry, Smoking, Odds ratio, Mendelian Randomization Analysis, medicine.disease, Confidence interval, 3. Good health, Causality, 030104 developmental biology, Estrogen, 030220 oncology & carcinogenesis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, ICEP, Colorectal Neoplasms, business, Genome-Wide Association Study
Abstract: Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer. Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls). Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00–1.26; P = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor–positive and estrogen receptor–negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04–1.40; P = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11–1.55; P < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07–1.73; P = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90–1.14; P = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86–1.10; P = 0.68). Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer. Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
Published: 2021

7. Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author: Amanda J. Cross, Kristin Benjaminsen Borch, Renée T. Fortner, Vittorio Simeon, Paul Brennan, Guri Skeie, Elio Riboli, Rosario Tumino, Elisabete Weiderpass, Gianluca Severi, Carlotta Sacerdote, Kim Overvad, Manuela M. Bergmann, Isabel Drake, Sara Grioni, Panagiota Pagoni, Giovanna Masala, Pietro Ferrari, Heinz Freisling, Matthias B. Schulze, Maria Dolores Chirlaque, Pilar Amiano, Mattias Johansson, Ioanna Tzoulaki, Konstantinos K. Tsilidis, Timothy J. Key, J. Ramón Quirós, Eva Ardanaz, Antonio Agudo, Neil Murphy, Marie-Christine Boutron-Ruault, Christel Häggström, Sofia Christakoudi, Rudolf Kaaks, Merete Ellingjord-Dale, Sophia Harlid, Charlotta Rylander, Tanja Stocks, Anne Tjønneland, Fanny Artaud, Laure Dossus, Jytte Halkjær, Miguel Rodríguez-Barranco, Aurora Perez-Cornago, David C. Muller, 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), 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, Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, CIRC National Research Council, NRC Medical Research Council, MRC: MC_UU_00011/6, MR/M012190/1 Cancer Research UK, CRUK: C570/A16491, C8221/A19170 World Cancer Research Fund, WCRF European Commission, EC Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Vetenskapsrådet, VR Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Rijksinstituut voor Volksgezondheid en Milieu, RIVM Institut Gustave-Roussy Mutuelle Générale de l'Education Nationale, MGEN NIHR Imperial Biomedical Research Centre, BRC Fondation Gustave Roussy, The authors thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC study. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Kr?ftens Bek?mpelse) (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid (Deutsche Krebshilfe), German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Federal Ministry of Education and Research (Bundesministerium f?r Bildung und Forschung, BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS-ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona) (Spain), Swedish Cancer Society (Cancerfonden), Swedish Research Council (Vetenskapsr?det), County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (MR/M012190/1 to EPIC-Oxford) (United Kingdom). Panagiota Pagoni is funded by Medical Research Council (grant reference MC_UU_00011/6). Infrastructure support for the Department of Epidemiology and Biostatistics at Imperial College London (UK) was provided by the NIHR Imperial Biomedical Research Centre (BRC). The funders had no role in the design and conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review and approval of the manuscript, or in the decision to submit the manuscript for publication., The authors thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC study. The coordination of EPIC is financially supported by the European Commission (DG‐SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Kræftens Bekæmpelse) (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid (Deutsche Krebshilfe), German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy and National Research Council (Italy), Health Research Fund (FIS‐ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona) (Spain), Swedish Cancer Society (Cancerfonden), Swedish Research Council (Vetenskapsrådet), County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (MR/M012190/1 to EPIC‐Oxford) (United Kingdom). Panagiota Pagoni is funded by Medical Research Council (grant reference MC_UU_00011/6). Infrastructure support for the Department of Epidemiology and Biostatistics at Imperial College London (UK) was provided by the NIHR Imperial Biomedical Research Centre (BRC). The funders had no role in the design and conduct of the study, the collection, analysis and interpretation of the data, or the preparation, review and approval of the manuscript, or in the decision to submit the manuscript for publication., Associazione Italiana per la Ricerca sul Cancro, Bundesministerium für Bildung und Forschung, Cancer Research UK, Grant/Award Numbers: C570/A16491, C8221/A19170, Cancerfonden, Catalan Institute of Oncology Barcelona, Centre International de Recherche sur le Cancer, County Council of Skåne Sweden, County Council of Västerbotten Sweden, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, Directorate‐General for Health and Consumers, Dutch Ministry of Public Health, Welfare and Sports (VWS), Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), Health Research Fund (FIS‐ISCIII) Spain, Institut Gustave‐Roussy, Institut National de la Santé et de la Recherche Médicale, Kræftens Bekæmpelse, Ligue Contre le Cancer, LK Research Funds, Medical Research Council, Grant/Award Numbers: MC_UU_00011/6, MR/M012190/1, Mutuelle Générale de l'Education Nationale, National Research Council Italy, Netherlands Cancer Registry, Regional Government of Andalucía, Regional Government of Asturias, Regional Government of Basque Country, Regional Government of Murcia, Regional Government of Navarra, Statistics Netherlands, Vetenskapsrådet, World Cancer Research Fund (WCRF), Institut Gustave Roussy, International Agency for Research on Cancer, European Commission (DG‐SANCO) Funding information, Christakoudi, S., Pagoni, P., Ferrari, P., Cross, A. J., Tzoulaki, I., Muller, D. C., Weiderpass, E., Freisling, H., Murphy, N., Dossus, L., Turzanski Fortner, R., Agudo, A., Overvad, K., Perez-Cornago, A., Key, T. J., Brennan, P., Johansson, M., Tjonneland, A., Halkjaer, J., Boutron-Ruault, M. -C., Artaud, F., Severi, G., Kaaks, R., Schulze, M. B., Bergmann, M. M., Masala, G., Grioni, S., Simeon, V., Tumino, R., Sacerdote, C., Skeie, G., Rylander, C., Borch, K. B., Quiros, J. R., Rodriguez-Barranco, M., Chirlaque, M. -D., Ardanaz, E., Amiano, P., Drake, I., Stocks, T., Haggstrom, C., Harlid, S., Ellingjord-Dale, M., Riboli, E., Tsilidis, K. K., and Cancer Research UK
Subjects: Male, Cancer Research, middle adulthood, Overweight, Body Mass Index, Cohort Studies, 0302 clinical medicine, Weight loss, Risk Factors, Neoplasms, Prospective Studies, Correlation of Data, 2. Zero hunger, Ovarian Neoplasms, Obstetrics, Hazard ratio, PROLIFERATION, WOMEN, weight gain, Middle Aged, Kidney Neoplasms, 3. Good health, European Prospective Investigation into Cancer and Nutrition, BMI change, Europe, Oncology, 030220 oncology & carcinogenesis, ddc:540, Female, SQUAMOUS-CELL CARCINOMA, medicine.symptom, Life Sciences & Biomedicine, EXPRESSION, medicine.medical_specialty, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, LEPTIN, FATNESS, medicine, Humans, cancer, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Obesity, Risk factor, Proportional Hazards Models, Cancer och onkologi, Science & Technology, business.industry, Weight change, Endometrial Neoplasms, BODY-MASS INDEX, ESTROGEN-RECEPTORS, Pancreatic Neoplasms, Nutrition Assessment, Cancer and Oncology, Institut für Ernährungswissenschaft, GAIN, weight loss, business, Weight gain, Body mass index
Abstract: International audience; Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
Published: 2021

8. Serologic markers of Chlamydia trachomatis and other sexually transmitted infections and subsequent ovarian cancer risk: Results from the EPIC cohort

Author: Agnès Fournier, Eva Lundin, N. Charlotte Onland-Moret, Louise Hansen, Elisavet Valanou, Marina Kvaskoff, Leire Gil, Inger T. Gram, Rosario Tumino, Marc J. Gunter, Annika Idahl, Rudolf Kaaks, Noemi Bender, Eric J. Duell, María José Sánchez, Carlotta Sacerdote, Kristian Riesbeck, Sandra González Maldonado, Claudia Agnoli, Anne Tjønneland, Charlotte Le Cornet, Renée T. Fortner, Laure Dossus, Marie-Christine Boutron-Ruault, Elisabete Weiderpass, Antonia Trichopoulou, Amalia Mattiello, José Ramón Quirós, Aurelio Barricarte, Maria Dolores Chirlaque, Tim Waterboer, Eleni Peppa, Domenico Palli, Jenny Brändstedt, Kay-Tee Khaw, Aurora Perez-Cornago, Heiner Boeing, Umeå University, Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Danish Cancer Society Research Center, Copenhagen, Denmark, parent, Centre de recherche en épidémiologie et santé des populations (CESP), 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), German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Hellenic Health Foundation, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Epidemiology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, I-20133 Milano, Italy, University of Naples Federico II, Civile - M.P.Arezzo Hospital, Center for Cancer Prevention (CPO-Piemonte), Universiteit Utrecht, Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway, Section of Cancer Surveillance, International Agency for Research on Cancer, Lyon, France. Electronic address: steliarova@iarc.fr., Catalan Institute of Oncology (ICO-IDIBELL), Hospitales Universitarios de Granada/Universidad de Granada, Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), CIBER de Epidemiología y Salud Pública (CIBERESP), IMIB-Arrixaca [Murcia, Spain], Universidad de Murcia, Public Health Institute of Navarra, Pamplona, Spain, and CIBER Epidemiología y Salud Pública (CIBERESP), IdiSNA, Navarra Institute for Health Research, Public Health Division of Gipuzkoa, Institute BIO Donostia-Health Department, Skane University Hospital [Lund], Department of Translational Medicine [Malmö, Sweden] (Clinical Microbiology), Lund University [Lund, Sweden], University of Cambridge [UK] (CAM), University of Oxford [Oxford], Ministerie van Volksgezondheid, Welzijn en Sport, VWS Deutsche Krebshilfe Cancer Research UK, CRUK: C8221/A19170, C570/A16491 VetenskapsrÃ¥det, VR Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Bundesministerium fÃ¼r Bildung und Forschung, BMBF Bundesministerium fÃ¼r Bildung und Forschung, BMBF Institut National de la Santé et de la Recherche Médicale, Inserm KrÃ¦ftens BekÃ¦mpelse, DCS CAN 2016/545 German Cancer Research Center, DKFZ National Research Council, NRC Cancer Research Foundation in Northern Sweden European Commission, EC Centre International de Recherche sur le Cancer, IARC RD06/0020 German Cancer Research Center, DKFZ Cancerfonden PI13/01162, PI13/00061 World Cancer Research Fund, WCRF: ERC-2009-AdG 232997 NordForsk Associazione Italiana per la Ricerca sul Cancro, AIRC Medical Research Council, MRC: MR/M012190/1, This work was supported by grants from The Cancer Research Foundation in Northern Sweden and The County Council of V?sterbotten, Sweden, and the German Cancer Research Center. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), the Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, and C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Additional funding received from the Anna and Edwin Berger Foundation (K.R.), Malm? Hospital Cancer Foundation (K.R.), Cancerfonden (CAN 2016/545 to K.R.).
Subjects: Oncology, Cancer Research, endocrine system diseases, Càncer d'ovari, Chlamydia trachomatis, Mycoplasma genitalium, Carcinoma, Ovarian Epithelial, medicine.disease_cause, Serology, 0302 clinical medicine, Risk Factors, Pelvic inflammatory disease, Prospective Studies, human papillomavirus, Aged, 80 and over, Ovarian Neoplasms, Sexually transmitted diseases, Human papillomavirus 16, Chlamydia, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, biology, Public Health, Global Health, Social Medicine and Epidemiology, Middle Aged, female genital diseases and pregnancy complications, 3. Good health, Serous fluid, ovarian cancer, 030220 oncology & carcinogenesis, Female, Malalties de transmissió sexual, Adult, Risk, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Ovarian cancer, Internal medicine, medicine, Humans, Neoplastic transformation, Aged, business.industry, Papillomavirus Infections, Chlamydia Infections, biology.organism_classification, medicine.disease, herpes simplex virus, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Relative risk, Case-Control Studies, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Biomarkers
Abstract: International audience; A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead-based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 [95% CI = 1.22-4.32]). Positive serology for chlamydia heat shock protein 60 (cHSP60-1) was associated with higher risk of EOC overall (1.36 [1.13-1.64]) and with the serous subtype (1.44 [1.12-1.85]). None of the other evaluated STIs were associated with EOC risk overall; however, HSV-2 was associated with higher risk of endometrioid EOC (2.35 [1.24-4.43]). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV-2 might promote the development of endometrioid disease.
Published: 2020

9. γ-Linolenic acid in maternal milk drives cardiac metabolic maturation

Author: Ana Paredes, Raquel Justo-Méndez, Daniel Jiménez-Blasco, Vanessa Núñez, Irene Calero, María Villalba-Orero, Andrea Alegre-Martí, Thierry Fischer, Ana Gradillas, Viviane Aparecida Rodrigues Sant’Anna, Felipe Were, Zhiqiang Huang, Pablo Hernansanz-Agustín, Carmen Contreras, Fernando Martínez, Emilio Camafeita, Jesús Vázquez, Jesús Ruiz-Cabello, Estela Area-Gómez, Fátima Sánchez-Cabo, Eckardt Treuter, Juan Pedro Bolaños, Eva Estébanez-Perpiñá, Francisco Javier Rupérez, Coral Barbas, José Antonio Enríquez, Mercedes Ricote, Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León (España), Ministerio de Ciencia e Innovación (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Swedish Research Council, Swedish Cancer Society (Cancerfonden), Novo Nordisk Foundation, Fondation Leducq, Fundación La Marató TV3, Ministerio de Economía y Competitividad (España), Fundación ProCNIC, and Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
Subjects: Multidisciplinary
Abstract: Birth presents a metabolic challenge to cardiomyocytes as they reshape fuel preference from glucose to fatty acids for postnatal energy production1,2. This adaptation is triggered in part by post-partum environmental changes3, but the molecules orchestrating cardiomyocyte maturation remain unknown. Here we show that this transition is coordinated by maternally supplied γ-linolenic acid (GLA), an 18:3 omega-6 fatty acid enriched in the maternal milk. GLA binds and activates retinoid X receptors4 (RXRs), ligand-regulated transcription factors that are expressed in cardiomyocytes from embryonic stages. Multifaceted genome-wide analysis revealed that the lack of RXR in embryonic cardiomyocytes caused an aberrant chromatin landscape that prevented the induction of an RXR-dependent gene expression signature controlling mitochondrial fatty acid homeostasis. The ensuing defective metabolic transition featured blunted mitochondrial lipid-derived energy production and enhanced glucose consumption, leading to perinatal cardiac dysfunction and death. Finally, GLA supplementation induced RXR-dependent expression of the mitochondrial fatty acid homeostasis signature in cardiomyocytes, both in vitro and in vivo. Thus, our study identifies the GLA-RXR axis as a key transcriptional regulatory mechanism underlying the maternal control of perinatal cardiac metabolism. Sí
Published: 2023

10. Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells

Author: Maria Häggblad, Silvana Mouron, Bartlomiej Porebski, Catherine Hansel, Louise Lidemalm, Pablo Martí-Rodrigo, Daniela Hühn, Jordi Carreras-Puigvert, Oscar Fernandez-Capetillo, Kirsten Tschapalda, Miguel Quintela-Fandino, Karolinska Institutet, Cancerfonden Foundation, Swedish Research Council, Instituto de Salud Carlos III, Unión Europea. Comisión Europea, and Comunidad de Madrid (España)
Subjects: PD-L1, Cancer Research, medicine.medical_treatment, Estrogen receptor, Breast Neoplasms, B7-H1 Antigen, Breast cancer, Immune system, breast cancer, INFLAMMATION, Cell Line, Tumor, Genetics, Medicine, Humans, IMMUNOTHERAPY, Research Articles, RC254-282, Cancer och onkologi, business.industry, Estrogen Antagonists, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Estrogens, General Medicine, Immunotherapy, medicine.disease, Antiestrogen, HLA, Cell killing, Phenotype, Oncology, inflammation, PD‐L1, Cancer and Oncology, Cancer research, Molecular Medicine, Female, immunotherapy, BREAST-CANCER PATIENTS, business, Janus kinase, Estrogen receptor alpha, Research Article, estrogen receptor
Abstract: Among others, expression levels of programmed cell death 1 ligand 1 (PD‐L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD‐L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD‐L1 downregulators. In addition, we identified that PD‐L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER‐positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen‐presenting machinery. Accordingly, estrogen‐deprived MCF7 cells are resistant to T‐cell‐mediated cell killing, in a manner that is independent of PD‐L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER‐positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion., Under prolonged hormone therapy, ER+ breast cancer cells activate an inflammatory transcriptional program, which includes a generalized upregulation of immune checkpoint mediators together with the downregulation of the antigen‐presenting machinery. These findings reveal that, while hormone therapies efficiently arrest the growth of ER+ breast cancer cells, they also promote a phenotype switch that favors their immune evasion.
Published: 2022

11. Major histocompatibility class I antigenic peptides derived from translation of pre-mRNAs generate immune tolerance

Author: Ewa Maria Sroka, Mathilde Lavigne, Marika Pla, Chrysoula Daskalogianni, Maria Camila Tovar-Fernandez, Rodrigo Prado Martins, Bénédicte Manoury, Guillaume Darrasse-Jéze, Megane Nascimento, Sebastien Apcher, Robin Fåhraeus, University of Gdańsk (UG), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Umeå University, INSERM, European Regional Development Fund (ENOCH, CZ.02.1.01/0.0/0.0/16_019/0000868), MH CZ – DRO (MMCI, 00209805), Cancerforskningsfonden Norr, Cancerfonden (160598), Vetenskapsradet and partially by the International Centre for Cancer Vaccine Science within the International Research Agendas program financed by the European Union under the European Regional Development Fund., and European Project: ERDF
Subjects: immune tolerance, mRNA translation, Multidisciplinary, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Immune tolerance, [SDV]Life Sciences [q-bio], Immunologi inom det medicinska området, Immunology in the medical area, MHC class I antigen presentation
Abstract: Antigenic peptides derived from introns are presented on major histocompatibility (MHC) class I molecules, but how these peptides are produced is poorly understood. Here, we show that an MHC class I epitope (SL8) sequence inserted in the second intron of the β-globin gene in a C57BL/6 mouse (HBB) generates immune tolerance. Introduction of SL8-specific CD8 + T cells derived from OT-1 transgenic mice resulted in a threefold increase in OT-1 T cell proliferation in HBB animals, as compared to wild-type animals. The growth of MCA sarcoma cells expressing the intron-derived SL8 epitope was suppressed in wild-type animals compared to HBB mice. The β-globin pre-mRNA was detected in the light polysomal fraction, and introducing stop codons identified a non-AUG initiation site between +228 and +255 nts upstream of the SL8. Isolation of ribosome footprints confirmed translation initiation within this 27 nt sequence. Furthermore, treatment with splicing inhibitor shifts the translation of the pre-mRNA to monosomal fractions and results in an increase of intron-derived peptide substrate as shown by polysome profiling and cell imaging. These results show that non-AUG-initiated translation of pre-mRNAs generates peptides for MHC class I immune tolerance and helps explain why alternative tissue-specific splicing is tolerated by the immune system.
Published: 2023

12. Lifestyle correlates of eight breast cancer-related metabolites: a cross-sectional study within the EPIC cohort

Author: Mathilde His, Vivian Viallon, Laure Dossus, Julie A. Schmidt, Ruth C. Travis, Marc J. Gunter, Kim Overvad, Cecilie Kyrø, Anne Tjønneland, Lucie Lécuyer, Joseph A. Rothwell, Gianluca Severi, Theron Johnson, Verena Katzke, Matthias B. Schulze, Giovanna Masala, Sabina Sieri, Salvatore Panico, Rosario Tumino, Alessandra Macciotta, Jolanda M. A. Boer, Evelyn M. Monninkhof, Karina Standahl Olsen, Therese H. Nøst, Torkjel M. Sandanger, Antonio Agudo, Maria-Jose Sánchez, Pilar Amiano, Sandra M. Colorado-Yohar, Eva Ardanaz, Linda Vidman, Anna Winkvist, Alicia K. Heath, Elisabete Weiderpass, Inge Huybrechts, Sabina Rinaldi, International Agency for Cancer Research (IACR), University of Oxford, Aarhus University [Aarhus], Danish Cancer Society Research Center [Copenhagen, Denmark] (DCSRC), University of Copenhagen = Københavns Universitet (UCPH), 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, Università degli Studi di Firenze = University of Florence (UniFI), Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke [Nuthetal, Germany] (GIHNP-R), University of Potsdam = Universität Potsdam, Istituto per lo Studio, la Prevenzione e la rete Oncologica [Florence, Italy] (ISPRO), IRCCS Istituto Nazionale dei Tumori [Milano], University of Naples Federico II = Università degli studi di Napoli Federico II, Provincial Health Authority (ASP 7) [Ragusa, Italy], Università degli studi di Torino = University of Turin (UNITO), National Institute for Public Health and the Environment [Bilthoven] (RIVM), University Medical Center [Utrecht], The Arctic University of Norway [Tromsø, Norway] (UiT), Catalan Institute of Oncology [Barcelone, Espagne], L’Hospitalet de Llobregat [Barcelona, Spain], Escuela Andaluza de Salud Pública [Granada, Spain] (EASP), Universidad de Granada = University of Granada (UGR), CIBER de Epidemiología y Salud Pública (CIBERESP), Public Health Division of Gipuzkoa, Basque Government, CIBER en Salud Pública, CIBERSP, Biodonostia Health Research Institute [Donostia-San Sebastian, Spain] (IIS Biodonostia), Murcia Regional Health Council [Murcia], Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Navarra Public Health Institute, Umeå University, Imperial College London, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Cancer Research UK, CRUK, World Cancer Research Fund, WCRF, University of Cambridge, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut National Du Cancer, INCa: 2015-166, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), and Cancer Research UK (14136 to EPIC-Norfolk (DOI 10.22025/2019.10.105.00004), C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143, MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The funders were not involved in designing the study, collecting, analyzing, or interpreting the data, or writing or submitting the manuscript for publication., The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)., This work was funded by the French National Cancer Institute (grant number 2015-166). Mathilde His’ work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC., The authors would like to thank Mr Bertrand Hemon for his support in preparing the databases, Ms Audrey Gicquiau and Dr David Achaintre for the analyses of samples in several of the original studies, and all EPIC participants. The EPIC-Norfolk team thank all the participants who have been part of the project and the many members of the study teams at the University of Cambridge who have enabled this research. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization., and HAL UVSQ, Équipe
Subjects: cross-sectional, lifestyle, Estils de vida, BIOMARKERS, Lifestyles, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, DIET, SERUM, Càncer de mama, Cohort Studies, Medicine, General & Internal, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Risk Factors, Cross-sectional, General & Internal Medicine, Metabolites, Humans, Metabolomics, Prospective Studies, VALIDITY, Life Style, 11 Medical and Health Sciences, metabolites, RISK, Cancer och onkologi, Science & Technology, anthropometry, Anthropometry, Public Health, Global Health, Social Medicine and Epidemiology, General Medicine, PROFILES, Lifestyle, AMINO-ACID, BODY-MASS INDEX, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, PHYSICAL-ACTIVITY, Cross-Sectional Studies, Metabolòmica, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cancer and Oncology, TARGETED METABOLOMICS, Medicine, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Life Sciences & Biomedicine, Research Article
Abstract: This work was funded by the French National Cancer Institute (grant number 2015-166). Mathilde His' work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); and Cancer Research UK (14136 to EPIC-Norfolk (DOI 10.22025/2019.10.105.00004); C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143, MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (UK). The funders were not involved in designing the study; collecting, analyzing, or interpreting the data; or writing or submitting the manuscript for publication., Background: Metabolomics is a promising molecular tool for identifying novel etiological pathways leading to cancer. In an earlier prospective study among pre- and postmenopausal women not using exogenous hormones, we observed a higher risk of breast cancer associated with higher blood concentrations of one metabolite (acetylcarnitine) and a lower risk associated with higher blood concentrations of seven others (arginine, asparagine, phosphatidylcholines (PCs) aa C36:3, ae C34:2, ae C36:2, ae C36:3, and ae C38:2). Methods: To identify determinants of these breast cancer-related metabolites, we conducted a cross-sectional analysis to identify their lifestyle and anthropometric correlates in 2358 women, who were previously included as controls in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition cohort and not using exogenous hormones at blood collection. Associations of each metabolite concentration with 42 variables were assessed using linear regression models in a discovery set of 1572 participants. Significant associations were evaluated in a validation set (n = 786). Results: For the metabolites previously associated with a lower risk of breast cancer, concentrations of PCs ae C34: 2, C36:2, C36:3, and C38:2 were negatively associated with adiposity and positively associated with total and saturated fat intakes. PC ae C36:2 was also negatively associated with alcohol consumption and positively associated with two scores reflecting adherence to a healthy lifestyle. Asparagine concentration was negatively associated with adiposity. Arginine and PC aa C36:3 concentrations were not associated to any of the factors examined. For the metabolite previously associated with a higher risk of breast cancer, acetylcarnitine, a positive association with age was observed. Conclusions: These associations may indicate possible mechanisms underlying associations between lifestyle and anthropometric factors, and risk of breast cancer. Further research is needed to identify potential non-lifestyle correlates of the metabolites investigated., Institut National du Cancer (INCA) France 2015-166, International Agency for Research on Cancer - Fondation ARC, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/N003284/1 MC-UU_12015/1 MC_UU_00006/1 MR/M012190/1
Published: 2021

13. Co-benefits from sustainable dietary shifts for population and environmental health: an assessment from a large European cohort study

Author: Manuela M. Bergmann, Tammy Y.N. Tong, Anna Stubbendorff, Elisabeth H. M. Temme, Claudia Agnoli, Ulrika Ericson, Antonio Agudo, Mélanie Deschasaux, Elisabete Weiderpass, Konstantinos K. Tsilidis, Dagfinn Aune, Guri Skeie, Giovanna Masala, Torkjel M. Sandanger, Emmanuelle Kesse-Guyot, Gianluca Severi, Charlotta Rylander, Francesca Mancini, Miguel A. Rodríguez Barranco, Marie-Christine Boutron-Ruault, Paolo Vineis, Mathilde Touvier, Pietro Ferrari, Marc J. Gunter, Daniel B Ibsen, Jolanda M. A. Boer, María José Pérez, Inge Huybrechts, Matthias B. Schulze, Anika Knuppel, Keren Papier, Elio Riboli, Bernard Srour, Christina C. Dahm, Jessica E. Laine, Tilmann Kühn, Medical Research Council (MRC), Imperial College London, University of Bern, Centre international de Recherche sur le Cancer (CIRC), Bjørknes University College [Oslo, Norvège], Oslo University Hospital [Oslo], University of Potsdam, German Institute of Human Nutrition Potsdam-Rehbruecke [Nuthetal, Germany] (GIHNP-R), National Institute for Public Health and the Environment [Bilthoven] (RIVM), IRCCS Istituto Nazionale dei Tumori [Milano], Lund University [Lund], Aarhus University [Aarhus], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Espace régional de réflexion éthique de Normandie (EREN), Escuela Andaluza de Salud Pública [Granada, Spain] (EASP), ibs.GRANADA Instituto de Investigación Biosanitaria [Granada, Spain], Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Granada [Granada], University of Oxford [Oxford], 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, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Istituto per lo Studio, la Prevenzione e la rete Oncologica [Florence, Italy] (ISPRO), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), The Arctic University of Norway (UiT), Italian Institute of Technology (IIT), International Arctic Research Center, University of Alaska, Fairbanks, IARC, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Wellcome Trust, WT: 205212/Z/16/Z, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, MR/M501669/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, The coordination of EPIC is financially supported by IARC and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre. The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, INSERM (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund, Statistics Netherlands (The Netherlands), Health Research Fund - Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), Medical Research Council (MRC, 1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford, UK). JEL was supported by an MRC Early Career Fellowship (MR/M501669/1). We acknowledge the Netherlands Cancer Registry and Statistics Netherlands (The Netherlands) for contributions to data acquisition. KP and AK are supported by the Wellcome Trust (Livestock, Environment and People, LEAP, grant number 205212/Z/16/Z). We acknowledge Corinne Casagrande and Genevieve Nicolas who assisted in the matching of the dietary intake data with the Greenhouse Gas and Landuse data. We also acknowledge Bertrand Hemon for database compilation and Carine Biessy for her contribution to the sensitivity analyses. Where authors are identified as personnel of the IARC or WHO, the authors alone are responsible for the views expressed in this Article and they do not necessarily represent the decisions, policy, or views of the IARC or WHO., Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, INSERM (France), Health Research Fund - Instituto de Salud Carlos III, Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), University of Potsdam = Universität Potsdam, Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Universidad de Granada = University of Granada (UGR), Nuffield Department of Population Health [Oxford], University of Oxford, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Università degli Studi di Firenze = University of Florence (UniFI), Institut Gustave Roussy (IGR), The Arctic University of Norway [Tromsø, Norway] (UiT), European Commission (DG-SANCO), the International Agency for Research on Cancer (IARC), MRC Early Career Fellowship (MR/M501669/1), and HAL UVSQ, Équipe
Subjects: Health (social science), 030309 nutrition & dietetics, [SDV]Life Sciences [q-bio], Population, Medicine (miscellaneous), 610 Medicine & health, Population health, Cohort Studies, Greenhouse Gases, 03 medical and health sciences, Clinical trials, 0302 clinical medicine, 360 Social problems & social services, Environmental health, 11. Sustainability, Canvi climàtic, Humans, Medicine, VDP::Medisinske Fag: 700, Prospective Studies, 030212 general & internal medicine, education, 2. Zero hunger, Public health, 0303 health sciences, education.field_of_study, Land use, business.industry, Health Policy, Hazard ratio, Public Health, Environmental and Occupational Health, Salut pública, Climatic change, Diet, 3. Good health, European Prospective Investigation into Cancer and Nutrition, [SDV] Life Sciences [q-bio], VDP::Medical disciplines: 700, Quartile, 13. Climate action, Greenhouse gas, Attributable risk, Dieta, business, Environmental Health, Assaigs clínics
Abstract: Funding European Commission (DG-SANCO) , the International Agency for Research on Cancer (IARC) , MRC Early Career Fellowship (MR/M501669/1) ., Background Unhealthy diets, the rise of non-communicable diseases, and the declining health of the planet are highly intertwined, where food production and consumption are major drivers of increases in greenhouse gas emissions, substantial land use, and adverse health such as cancer and mortality. To assess the potential co-benefits from shifting to more sustainable diets, we aimed to investigate the associations of dietary greenhouse gas emissions and land use with all-cause and cause-specific mortality and cancer incidence rates. Methods Using data from 443 991 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a multicentre prospective cohort, we estimated associations between dietary contributions to greenhouse gas emissions and land use and all-cause and cause-specific mortality and incident cancers using Cox proportional hazards regression models. The main exposures were modelled as quartiles. Co-benefits, encompassing the potential effects of alternative diets on all-cause mortality and cancer and potential reductions in greenhouse gas emissions and land use, were estimated with counterfactual attributable fraction intervention models, simulating potential effects of dietary shifts based on the EAT–Lancet reference diet. Findings In the pooled analysis, there was an association between levels of dietary greenhouse gas emissions and allcause mortality (adjusted hazard ratio [HR] 1·13 [95% CI 1·10–1·16]) and between land use and all-cause mortality (1·18 [1·15–1·21]) when comparing the fourth quartile to the first quartile. Similar associations were observed for cause-specific mortality. Associations were also observed between all-cause cancer incidence rates and greenhouse gas emissions, when comparing the fourth quartile to the first quartile (adjusted HR 1·11 [95% CI 1·09–1·14]) and between all-cause cancer incidence rates and land use (1·13 [1·10–1·15]); however, estimates differed by cancer type. Through counterfactual attributable fraction modelling of shifts in levels of adherence to the EAT–Lancet diet, we estimated that up to 19–63% of deaths and up to 10–39% of cancers could be prevented, in a 20-year risk period, by different levels of adherence to the EAT–Lancet reference diet. Additionally, switching from lower adherence to the EAT–Lancet reference diet to higher adherence could potentially reduce food-associated greenhouse gas emissions up to 50% and land use up to 62%. Interpretation Our results indicate that shifts towards universally sustainable diets could lead to co-benefits, such as minimising diet-related greenhouse gas emissions and land use, reducing the environmental footprint, aiding in climate change mitigation, and improving population health., European Commission European Commission Joint Research Centre, World Health Organization, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/M501669/1
Published: 2021

14. Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study

Author: Eva Ardanaz, Agnetha Linn Rostgaard-Hansen, Alessio Naccarati, Elisabete Weiderpass, Pekka Keski-Rahkonen, Rudolf Kaaks, Tilman Kühn, Anna Winkvist, Jośe Mariá Huerta, H. B. Bueno-De-Mesquita, Guri Skeie, Pietro Ferrari, Krasimira Aleksandrova, Gabriel Perlemuter, Augustin Scalbert, Olatz Mokoroa, Giovanna Tagliabue, Marc J. Gunter, Kim Overvad, José Ramón Quirós, Agneta Kiss, Marie-Christine Boutron-Ruault, Yahya Mahamat-Saleh, Talita Duarte-Salles, Nivonirina Robinot, Anne Tjønneland, Antonia Trichopoulou, Julie A. Schmidt, Christina C. Dahm, Roel Vermeulen, Rosario Tumino, Núria Sala, Joseph A. Rothwell, Sophia Harlid, Magdalena Stepien, Klas Sjöberg, Vivian Viallon, Neil Murphy, Anna Karakatsani, Salvatore Panico, Nicholas J. Wareham, María José Sánchez, Francesca Mancini, Domenico Palli, Mazda Jenab, Elio Riboli, Bodil Ohlsson, Kay-Tee Khaw, Centre de recherche en épidémiologie et santé des populations (CESP), 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), Institut National Du Cancer, INCa: 2014-1-RT-02-CIRC-1 Ministerie van Volksgezondheid, Welzijn en Sport, VWS Cancer Research UK, CRUK: C570/A16491 Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer German Cancer Research Center, DKFZ Bundesministerium für Bildung und Forschung, BMBF Institut National de la Santé et de la Recherche Médicale, Inserm Kræftens Bekæmpelse, DCS National Research Council, NRC 6236 Hellenic Health Foundation, HHF Fondation Gustave Roussy European Commission, EC Centre International de Recherche sur le Cancer, CIRC Associazione Italiana per la Ricerca sul Cancro, AIRC RD06/0020 Deutsche Krebshilfe World Cancer Research Fund, WCRF Cancerfonden Medical Research Council, MRC: MR/M012190/1, This work was supported by the French National Cancer Institute (L'Institut National du Cancer, INCA) (grant number 2014-1-RT-02-CIRC-1, PI: M. Jenab). The coordination of EPIC is financially supported by the European Commission (DG-SANCO), and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, and Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ), and Federal Ministry of Education and Research (Germany), Hellenic Health Foundation (Greece), Italian Association for Research on Cancer (AIRC), National Research Council, and AIRE-ONLUS Ragusa, AVIS Ragusa, Sicilian Government (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands), and Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia (No. 6236) and Navarra, and ISCIII RETIC (RD06/0020) and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 for EPIC-Norfolk and C570/A16491 for EPIC-Oxford) and the Medical Research Council (1000143 for EPIC-Norfolk and MR/M012190/1 for EPIC-Oxford) (UK). The funding sources had no influence on the design of the study, the collection, analysis, and interpretation of data, the writing of the report, and or the decision to submit the paper for publication. Disclaimer: Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization.
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, prospective observational cohort, Glycocholic acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mass Spectrometry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Dehydroepiandrosterone sulfate, Internal medicine, Biomarkers, Tumor, medicine, Humans, Metabolomics, Prospective Studies, Aged, Hepatitis, business.industry, Liver Neoplasms, Cancer, Feeding Behavior, hepatocellular carcinoma, Middle Aged, medicine.disease, 3. Good health, European Prospective Investigation into Cancer and Nutrition, untargeted metabolomics, chemistry, Case-Control Studies, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cohort, Female, business, Metabolic Networks and Pathways, Chromatography, Liquid, Cohort study
Abstract: International audience; Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
Published: 2020

15. Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study

Author: Pietro Ferrari, Fulvio Ricceri, Christina C. Dahm, Kim Overvad, Sabina Sieri, Elisabete Weiderpass, Eleni Peppa, María José Sánchez, Leila Luján Barroso, Marta Solans Margalef, Matthias B. Schulze, Federico Canzian, Giovanna Masala, Florentin Spaeth, Dagfinn Aune, Roel Vermeulen, Tilman Kühn, Delphine Casabonne, Karin Jirstom, Anna Karakatsani, José María Huerta, Yahya Mahamat-Saleh, Paul Brennan, Cecilie Kyrø, Mats Jerkeman, Caroline Besson, Pilar Amiano Exezarreta, Virginia Menéndez, Elio Riboli, Julie A. Schmidt, Rosario Tumino, Sairah L.F. Chen, Marc J. Gunter, Eva Ardanaz, Antonia Trichopoulou, Alexandra Nieters, Marie-Christine Boutron-Ruault, Anne Tjønneland, Fatemeh Saberi Hosnijeh, Sabine Naudin, Salvatore Panico, Centre international de Recherche sur le Cancer (CIRC), 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 Hospitalier de Versailles André Mignot (CHV), Direction Générale de la Compétitivité, de l’Industrie et des Services, DGCIS Food Standards Agency, FSA Cancer Research UK, CRUK: C864/A14136, C8221/A19170, C570/A16491 RD06/0020 Ministerie van Volksgezondheid, Welzijn en Sport, VWS Université Claude Bernard Lyon 1, UCBL Wellcome Trust, WT Ligue Contre le Cancer 6236 German Cancer Research Center, DKFZ Bundesministerium für Bildung und Forschung, BMBF Department of Health, Australian Government Ministry of Health and Social Solidarity, Greece Kræftens Bekæmpelse, DCS British Heart Foundation, BHF Instituto de Salud Carlos III, ISCIII National Research Council, NRC Mutuelle Générale de l'Education Nationale, MGEN Hellenic Health Foundation, HHF Stroke Association Institut National de la Santé et de la Recherche Médicale, Inserm Fondation Gustave Roussy European Commission, EC Centre International de Recherche sur le Cancer, IARC Deutsche Krebshilfe Cancerfonden World Cancer Research Fund, WCRF Stavros Niarchos Foundation, SNF Ministère des Affaires Sociales et de la Santé: GR‐IARC‐2003‐09‐12‐01 Medical Research Council, MRC: MR/M012190/1, MR/N003284/1, MC‐UU_12015/1, We thank Carine Biessy and Bertrand Hemon for their technical support and contribution to this work. We are also grateful to all the EPIC participants who have been part of the project and to the many other members of the study teams who have enabled this research. This work was supported by the Direction Générale de la Santé (French Ministry of Health, Grant GR‐IARC‐2003‐09‐12‐01), by the European Commission (Directorate General for Health and Consumer Affairs) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark), the Ligue Contre le Cancer, the Institut Gustave Roussy, the Mutuelle Générale de l'Education Nationale and the Institut National de la Santé et de la Recherche Médicale (France), the Deutsche Krebshilfe, the Deutsches Krebsforschungszentrum and the Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity (Greece), the Italian Association for Research on Cancer and the National Research Council (Italy), the Dutch Ministry of Public Health, Welfare and Sports, the Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, the Dutch Zorg Onderzoek Nederland, the World Cancer Research Fund and Statistics Netherlands (the Netherlands), the Health Research Fund, Regional Governments of Andalucýa, Asturias, Basque Country, Murcia (project 6236) and Navarra, Instituto de Salud Carlos III, Redes de Investigacion Cooperativa (RD06/0020, Spain), the Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skåne (Sweden), Cancer Research UK (C864/A14136 to EPIC‐Norfolk, C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (MR/N003284/1 and MC‐UU_12015/1 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford, and United Kingdom), the Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust (UK). This work was part of Sabine Naudin's PhD at Claude Bernard Lyon I University (France), funded by Région Auvergne Rhône‐Alpes, ADR 2016 (France).
Subjects: Male, Oncology, Cancer Research, Lymphoma, Body Mass Index, 0302 clinical medicine, Risk Factors, immune system diseases, hemic and lymphatic diseases, Prospective Studies, Prospective cohort study, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Incidence, non-Hodgkin lymphoma, Smoking, Hazard ratio, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, 030220 oncology & carcinogenesis, Female, EPIC, healthy lifestyle index, Hodgkin lymphoma, prospective study, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Alcohol Drinking, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diet Surveys, 03 medical and health sciences, Internal medicine, REGRESSION, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Healthy Lifestyle, Exercise, Aged, Science & Technology, business.industry, Proportional hazards model, HODGKINS-LYMPHOMA, Feeding Behavior, medicine.disease, Confidence interval, Etiology, UPDATE, CIGARETTE-SMOKING, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Follow-Up Studies
Abstract: This is the peer reviewed version of the following article: Naudin, S., Margalef, M.S., Hosnijeh, F.S., Nieters, A., Kyrø, C. Tjønneland, A. ... Ferrari, P. (2020) Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study. International Journal of Cancer, 147(6):1649-1656, which has been published in final form at https://doi.org/10.1002/ijc.32977. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) were evaluated in a large‐scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow‐up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1‐standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1‐SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.
Published: 2020

16. CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway

Author: Daniel Gómez-Cabello, George Pappas, Diana Aguilar-Morante, Christoffel Dinant, Jiri Bartek, Universidad de Sevilla. Departamento de Genética, Danish Cancer Society. Demmark, Lundbeck Foundation, Danish Council for Independent Research. Demmark, Novo Nordisk Foundation, Swedish Research Council, Swedish Cancer Foundation/Cancerfonden. Sweden, Danish National Research Foundation, Danish Cancer Society Research Center, Danish Council for Independent Research, Swedish Cancer Society, European Commission, Asociación Española Contra el Cáncer, Gómez-Cabello, Daniel, Pappas, George, Aguilar Morante, Diana, and Bartek, Jiri
Subjects: DNA End-Joining Repair, Multidisciplinary, DNA Repair, Recombinational DNA Repair, General Physics and Astronomy, Genetic mapping, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Mechanisms of disease, Targeted therapies, Cancer genomics, Humans, RNA, DNA Breaks, Double-Stranded, RNA Polymerase II, Super-resolution microscopy
Abstract: The RNA world is changing our views about sensing and resolution of DNA damage. Here, we develop single-molecule DNA/RNA analysis approaches to visualize how nascent RNA facilitates the repair of DNA double-strand breaks (DSBs). RNA polymerase II (RNAPII) is crucial for DSB resolution in human cells. DSB-flanking, RNAPII-generated nascent RNA forms RNA:DNA hybrids, guiding the upstream DNA repair steps towards favouring the error-free Homologous Recombination (HR) pathway over Non-Homologous End Joining. Specific RNAPII inhibitor, THZ1, impairs recruitment of essential HR proteins to DSBs, implicating nascent RNA in DNA end resection, initiation and execution of HR repair. We further propose that resection factor CtIP interacts with and helps re-activate RNAPII when paused by the RNA:DNA hybrids, collectively promoting faithful repair of chromosome breaks to maintain genomic integrity., This work was supported by The Danish Cancer Society (R1123-A7785-15-S2), The Lundbeck Foundation (R266-2017-4289), The Danish Council for Independent Research (#DFF-7016-00313), The Novo Nordisk Foundation: synergy grants 16854 and NNF20OC0060590, The Swedish Research Council VR-MH 2014-46602-117891-30, The Swedish Cancer Foundation/Cancerfonden (#170176), and The Danish National Research Foundation (project CARD, DNRF 125). D.G.-C. has been awarded with MSCA-IF-2017 (795930), Lundbeck Foundation (R250-2017-584 and R252-2017-1567) and AECC-Investigator Grant (INVES20017GOME). G.P. is a recipient of a MSCA-ITN.
Published: 2022

17. Pre-diagnostic C-reactive protein concentrations, CRP genetic variation and mortality among individuals with colorectal cancer in Western European populations

Author: Katharina Nimptsch, Krasimira Aleksandrova, Veronika Fedirko, Mazda Jenab, Marc J. Gunter, Peter D. Siersema, Kana Wu, Verena Katzke, Rudolf Kaaks, Salvatore Panico, Domenico Palli, Anne M May, Sabina Sieri, Bas Bueno-de-Mesquita, Karina Standahl, Maria-Jose Sánchez, Aurora Perez-Cornago, Anja Olsen, Anne Tjønneland, Catalina Bonet Bonet, Christina C. Dahm, María-Dolores Chirlaque, Valentina Fiano, Rosario Tumino, Aurelio Barricarte Gurrea, Marie-Christine Boutron-Ruault, Florence Menegaux, Gianluca Severi, Bethany van Guelpen, Young-Ae Lee, Tobias Pischon, HAL UVSQ, Équipe, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Harvard T.H. Chan School of Public Health, Leibniz Institute for Prevention Research and Epidemiology - BIPS, Leibniz Association, University of Bremen, The University of Texas M.D. Anderson Cancer Center [Houston], Emory University [Atlanta, GA], 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), Radboud University Medical Center [Nijmegen], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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, World Health Organization, WHO, Cancer Prevention and Research Institute of Texas, CPRIT: RR200056, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, Consejería de Salud y Familias, Junta de Andalucía, NIHR Imperial Biomedical Research Centre, BRC, We acknowledge the use of data and biological samples from the EPIC-Asturias cohort, PI Jose-Ramon Quiros-Garcia and EPI-San Sebastian, PI Amiano Pilar. Veronika Fedirko is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award (Grant ID RR200056). Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization., The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (C8221/A29017 to EPIC-Oxford), Medical Research Council (MR/M012190/1 to EPIC-Oxford) (United Kingdom). The EPIC-Norfolk study (DOI https://doi.org/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). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research., The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)., and We acknowledge the use of data and biological samples from the EPIC-Asturias cohort, PI Jose-Ramon Quiros-Garcia and EPI-San Sebastian, PI Amiano Pilar. Veronika Fedirko is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award (Grant ID RR200056).
Subjects: Cancer Research, Cancer och onkologi, Public Health, Global Health, Social Medicine and Epidemiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], C-Reactive Protein, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiovascular and Metabolic Diseases, Risk Factors, Cancer and Oncology, Genetics, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genetic Predisposition to Disease, Prospective Studies, Colorectal Neoplasms
Abstract: Background The role of elevated pre-diagnostic C-reactive protein (CRP) concentrations on mortality in individuals with colorectal cancer (CRC) remains unclear. Methods We investigated the association between pre-diagnostic high-sensitivity CRP concentrations and CRP genetic variation associated with circulating CRP and CRC-specific and all-cause mortality based on data from 1,235 individuals with CRC within the European Prospective Investigation into Cancer and Nutrition cohort using multivariable-adjusted Cox proportional hazards regression. Results During a median follow-up of 9.3 years, 455 CRC-specific deaths were recorded, out of 590 deaths from all causes. Pre-diagnostic CRP concentrations were not associated with CRC-specific (hazard ratio, HR highest versus lowest quintile 0.92, 95% confidence interval, CI 0.66, 1.28) or all-cause mortality (HR 0.91, 95% CI 0.68, 1.21). Genetic predisposition to higher CRP (weighted score based on alleles of four CRP SNPs associated with higher circulating CRP) was not significantly associated with CRC-specific mortality (HR per CRP-score unit 0.95, 95% CI 0.86, 1.05) or all-cause mortality (HR 0.98, 95% CI 0.90, 1.07). Among four investigated CRP genetic variants, only SNP rs1205 was significantly associated with CRC-specific (comparing the CT and CC genotypes with TT genotype, HR 0.54, 95% CI 0.35, 0.83 and HR 0.58, 95% CI 0.38, 0.88, respectively) and all-cause mortality (HR 0.58, 95% CI 0.40, 0.85 and 0.64, 95% CI 0.44, 0.92, respectively). Conclusions The results of this prospective cohort study do not support a role of pre-diagnostic CRP concentrations on mortality in individuals with CRC. The observed associations with rs1205 deserve further scientific attention.
Published: 2022

18. Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition

Author: Marie Breeur, Pietro Ferrari, Laure Dossus, Mazda Jenab, Mattias Johansson, Sabina Rinaldi, Ruth C. Travis, Mathilde His, Tim J. Key, Julie A. Schmidt, Kim Overvad, Anne Tjønneland, Cecilie Kyrø, Joseph A. Rothwell, Nasser Laouali, Gianluca Severi, Rudolf Kaaks, Verena Katzke, Matthias B. Schulze, Fabian Eichelmann, Domenico Palli, Sara Grioni, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Bas Bueno-de-Mesquita, Karina Standahl Olsen, Torkjel Manning Sandanger, Therese Haugdahl Nøst, J. Ramón Quirós, Catalina Bonet, Miguel Rodríguez Barranco, María-Dolores Chirlaque, Eva Ardanaz, Malte Sandsveden, Jonas Manjer, Linda Vidman, Matilda Rentoft, David Muller, Kostas Tsilidis, Alicia K. Heath, Hector Keun, Jerzy Adamski, Pekka Keski-Rahkonen, Augustin Scalbert, Marc J. Gunter, Vivian Viallon, Cancer Research UK, 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), 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, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC: 2014/1183, C8221/A19170, Seventh Framework Programme, FP7: 2014/1193, 313010, C19335/A21351, National Research Council, NRC, World Cancer Research Fund International, WCRF, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, European Commission, EC, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Generalitat de Catalunya, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Fondation ARC pour la Recherche sur le Cancer, ARC, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut National Du Cancer, INCa: 2009-139, 2013/1002, 2014-1-RT-02-CIRC-1, 2015-166, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, Consejería de Salud y Familias, Junta de Andalucía, NIHR Imperial Biomedical Research Centre, BRC, The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC)., This paper is dedicated to the memory our of colleague Dr. Bas Bueno-de-Mesquita. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization., The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). IDIBELL acknowledges support from the Generalitat de Catalunya through the CERCA Program. The breast cancer study was funded by the French National Cancer Institute (grant number 2015-166). The colorectal cancer studies were funded by World Cancer Research Fund (reference: 2013/1002, reference: 313010, reference: 2014/1193, INCa, grant numbers 2009-139 and 2014-1-RT-02-CIRC-1) and by internal funds of the IARC. For the participants in the prostate cancer study, sample retrieval and preparation, and assays of metabolites were supported by Cancer Research UK (C8221/A19170), and funding for grant 2014/1183 was obtained from the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme. Mathilde His’ work reported here was undertaken during the tenure of a postdoctoral fellowship awarded by the International Agency for Research on Cancer, financed by the Fondation ARC. The funders were not involved in designing the study, collecting, analysing, and interpreting results, or writing and submitting the manuscript for publication., and HAL UVSQ, Équipe
Subjects: Male, Carcinoma, Hepatocellular, Proline, Glutamine, Kidney, Risk Factors, General & Internal Medicine, Humans, Metabolomics, Histidine, Prospective Studies, Breast, Càncer, 11 Medical and Health Sciences, Colorectal, Cancer, Cancer och onkologi, Liver Neoplasms, Prostate, Lysophosphatidylcholines, General Medicine, Sphingomyelins, Metabolòmica, Liver, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Cancer and Oncology, Carcinoma, Hepatocellular/diagnosis, Phosphatidylcholines, Epic, Endometrial, Lasso, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, EPIC
Abstract: Background Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. Methods We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. Results Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. Conclusions These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.
Published: 2022

19. Dietary fatty acids, macronutrient substitutions, food sources and incidence of coronary heart disease: Findings from the EPIC-CVD case-cohort study across nine european countries

Author: Matthias B. Schulze, Vittorio Krogh, Rosario Tumino, Nita G. Forouhi, Christina C. Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Angela M. Wood, Yvonne T. van der Schouw, Guri Skeie, Laura Johnson, Fumiaki Imamura, Ivonne Sluijs, José R Quirós, Elisabete Weiderpass, Nicholas J. Wareham, Timothy J. Key, Adam S. Butterworth, Giovanna Masala, Alicia K Heath, Albert Koulman, Conchi Moreno-Iribas, Inge Huybrechts, John Danesh, Stephen J. Sharp, Salvatore Panico, Carlotta Sacerdote, Aurora Perez-Cornago, Olle Melander, Rudolf Kaaks, Elio Riboli, Tammy Y.N. Tong, María José Sánchez, Rajiv Chowdhury, Ju-Sheng Zheng, Miguel Rodríguez-Barranco, W M Monique Verschuren, Marinka Steur, Ingegerd Johansson, Heiner Boeing, Anne Tjønneland, Carmen Santiuste, Antonia Trichopoulou, Maria Wennberg, Jolanda M. A. Boer, Marcela Guevara, Cecilie Kyrø, Raul Zamora-Ros, Liher Imaz, Tilman Kühn, Marianne Uhre Jakobsen, Ulrika Ericson, 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), 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, G0800270, MR/L003120/1, Pfizer, AstraZeneca, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, Merck Sharp and Dohme, MSD, Seventh Framework Programme, FP7: HEALTH-F2-2012-279233, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MC_UU_00006/1, National Institute for Health Research, NIHR, British Heart Foundation, BHF: RG/18/13/33946, RG13/13/30194, SP/09/002, Cancer Research UK, CRUK: C8221/A29017, MR/M012190/1, World Cancer Research Fund, WCRF, Imperial College London, European Research Council, ERC: 268834, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, European Social Fund, ESF, Sixth Framework Programme, FP6: LSHM_CT_2006_037197, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Akademi Sains Malaysia, ASM: MR/P013880/1, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, UCLH Biomedical Research Centre, NIHR BRC: BRC-1215-20014, NIHR Imperial Biomedical Research Centre, BRC, Hellenic Health Foundation, HHF: CP15/00100, IS-BRC-1215-20014, MC_UU_00006/3, Dr Danesh reports grants, personal fees and non-financial support from Merck Sharp & Dohme, grants, personal fees, and nonfinancial support from Novartis, grants from Pfizer, and grants from AstraZeneca outside the submitted work. He is member of the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis, and the Astra Zeneca Genomics Advisory Board (2018). Dr Butterworth reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer, and Sanofi and personal fees from Novartis. The remaining authors have no disclosures to report., EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270, MR/L003120/1), British Heart Foundation (BHF) (SP/09/002, RG13/13/30194, RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), 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 (the Netherlands), Health Research Fund– Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R.Z.-R. thanks the 'Miguel Servet' program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund–European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart). R.C. was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award., Steur, Marinka [0000-0002-9028-0290], Imamura, Fumiaki [0000-0002-6841-8396], Key, Timothy J [0000-0003-2294-307X], Chowdhury, Rajiv [0000-0003-4881-5690], Guevara, Marcela [0000-0001-9242-6364], Jakobsen, Marianne U [0000-0001-6518-4136], Johansson, Ingegerd [0000-0002-9227-8434], Weiderpass, Elisabete [0000-0003-2237-0128], Boer, Jolanda MA [0000-0002-9714-4304], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Heath, Alicia K [0000-0001-6517-1300], Huybrechts, Inge [0000-0003-3838-855X], Imaz, Liher [0000-0002-3777-4953], Masala, Giovanna [0000-0002-5758-9069], Zamora-Ros, Raul [0000-0002-6236-6804], Perez-Cornago, Aurora [0000-0002-5652-356X], Tong, Tammy YN [0000-0002-0284-8959], Wareham, Nicholas J [0000-0003-1422-2993], Forouhi, Nita G [0000-0002-5041-248X], and Apollo - University of Cambridge Repository
Subjects: Saturated fat, Physiology, Coronary Disease, 030204 cardiovascular system & hematology, EPIC, Cohort Studies, 0302 clinical medicine, Medicine, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, 2. Zero hunger, chemistry.chemical_classification, Nutrition and Dietetics, Kardiologi, Primary prevention, Incidence, Incidence (epidemiology), Fatty Acids, Fatty acids in human nutrition, 3. Good health, Europe, Näringslära, Coronary heart disease, Dietary guidelines, Cardiology and Cardiovascular Medicine, Polyunsaturated fatty acid, Cohort study, Malalties coronàries, 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Àcids grassos en la nutrició, Diseases of the circulatory (Cardiovascular) system, Humans, Nutritional epidemiology, business.industry, Nutrients, Dietary Fats, chemistry, Food, RC666-701, SPS Exercise, Nutrition and Health Sciences, business
Abstract: EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270; MR/L003120/1), British Heart Foundation (BHF) (SP/09/002; RG13/13/30194; RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_ 2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro--AIRC--Italy, Compagnia di SanPaolo and National Research Council (Italy); 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 (the Netherlands); Health Research Fund-Instituto de Salud Carlos III, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_ 00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215--20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R. Z.-R. thanks the "Miguel Servet" program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund--European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart).R.C.was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The funders of the study had no role in study design, data collection, analysis, data interpretation, or writing of the article, or in the decision to submit for publication. M.S. had full access to all the data in the study, and M.S. and N.G.F. had final responsibility for the decision to submit for publication., BACKGROUND: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. METHODS AND RESULTS: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). CONCLUSIONS: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix., European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), European Commission 268834, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) G0800270 MR/L003120/1, British Heart Foundation SP/09/002 RG13/13/30194 RG/18/13/33946, National Institute for Health Research (NIHR) BRC-1215-20014, European Commission LSHM_CT_ 2006_037197, Medical Research Council UK (MRC) MC_UU_ 00006/1 MC_UU_00006/3, International Agency for Research on Cancer, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam, Rehbruecke, Federal Ministry of Education and Research (Germany), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III, Junta de Andalucia, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology (Spain), Swedish Cancer Society, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, Medical Research Council UK (MRC) 1000143 MR/M012190/1, Hellenic Health Foundation (Greece), NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, Institute of Health Carlos III (European Social Fund-European Social Fund Investing in Your Future) CP15/00100, BHF-Turing Cardiovascular Data Science Award, European Commission-Innovative Medicines Initiative (BigData@Heart), MRC-Newton project grant MR/P013880/1, United Kingdom Research and Innovation-Global Challenges Research Fund, NIHR Senior Investigator Award
Published: 2021

20. Pre-diagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma

Author: Heinz Freisling, Susana Merino, Aurelio Barricarte, Augustin Scalbert, Domenico Palli, Eleni Peppa, Hanna Nyström, Klas Sjöberg, Magdalena Stepien, Antonia Trichopoulou, Aurora Perez-Cornago, Marina Lopez-Nogueroles, Gianluca Severi, Carlotta Sacerdote, Dragos Ciocan, Tilman Kühn, Elisabete Weiderpass, Cosmin Sebastian Voican, Manuela M. Bergmann, Gabriel Perlemuter, Eugene Jansen, Rudolf Kaaks, Michael F. Leitzmann, Julie A. Schmidt, Catherine Dong, Anna Karakatsani, María José Sánchez, Rosario Tumino, Bodil Ohlsson, H. Bas Bueno-de-Mesquita, Marc J. Gunter, Raul Zamora Ros, Guri Skeie, José Mª Huerta, Heiner Boeing, Agustín Lahoz, Vittorio Krogh, Pilar Amiano, Francesca Mancini, Anne Tjønneland, Marie-Christine Boutron-Ruault, Salvatore Panico, Mazda Jenab, Sofia Christakoudi, Vivian Viallon, Renée T. Fortner, Mårten Werner, Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Department of Radiology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, 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, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: 1000143, MR/M012190/1, Cancer Research UK, CRUK: 14136, C8221/A29017, World Cancer Research Fund, WCRF, University of Cambridge, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Deutsche Krebshilfe, Institut National Du Cancer, INCa: 2009‐139, 2014‐1‐RT‐02‐CIRC‐1, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, This work was supported in part by the French National Cancer Institute (L'Institut National du Cancer, INCa, grant numbers 2009‐139 and 2014‐1‐RT‐02‐CIRC‐1, PI: M. Jenab) and by internal funds of the IARC. The coordination of EPIC is financially supported by the International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam‐Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC‐Norfolk, C8221/A29017 to EPIC‐Oxford), Medical Research Council (1000143 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford) (United Kingdom). The funding sources had no influence on the design of the study, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the article for publication. Funding information, and We would like to acknowledge Dr Krasimira Aleksandrova for input on the present manuscript, along with the National Institute for Public Health and the Environment (Bilthoven, The Netherlands), the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands, Department of Public Health Aarhus University (Aarhus, Denmark), University of Cambridge (Cambridge, United Kingdom), for their contributions and ongoing support to the EPIC Study.
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, obesity, Carcinoma, Hepatocellular, medicine.drug_class, education, [SDV.CAN]Life Sciences [q-bio]/Cancer, Gastroenterology, Bile Acids and Salts, Cohort Studies, chemistry.chemical_compound, Internal medicine, medicine, Biomarkers, Tumor, Choline, Humans, Prospective cohort study, Carcinogen, Aged, Cancer prevention, Bile acid, cancer prevention, business.industry, Confounding, Liver Neoplasms, bile acid metabolism, biomarkers, hepatocellular carcinoma, Middle Aged, medicine.disease, Obesity, Oncology, chemistry, Hepatocellular carcinoma, Case-Control Studies, Female, business
Abstract: This is the peer reviewed version of the following article: Stepien et.al (2021). Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma. International Journal of Cancer, which has been published in final form at https://doi.org/10.1002/ijc.33885. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
Published: 2021

21. The different activities of RNA G-quadruplex structures are controlled by flanking sequences

Author: Alice J-L Zheng, Anton Granzhan, Nathan Vaudiau, Chrysoula Daskalogianni, Robin Fåhraeus, Rodrigo Prado Martins, Aikaterini Thermou, Marc Blondel, Petter Brohagen, Marie-Paule Teulade-Fichou, Laurence Malbert-Colas, Pedro Guixens Gallardo, Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), International Centre for Cancer Vaccine Science (ICCVS), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Infectiologie et Santé Publique (UMR ISP), Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Masaryk Memorial Cancer Institute (RECAMO), Department of Medical Biosciences [Umeå, Suède], Umeå University, European Regional Development Fund (ENOCH)CZ.02.1.01/0.0/0.0/16_019/0000868, MH CZ-DRO (MMCI, 00209805), Cancerforskningsfonden Norr, Cancerfonden 160598, Swedish Research Council, International Centre for Cancer Vaccine Science within the International Research Agendas program of the Foundation for Polish Science, Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Masaryk Memorial Cancer Institute (MMCI), and Chanteloup, Nathalie Katy
Subjects: G4 RNA structure, Health, Toxicology and Mutagenesis, Plant Science, Computational biology, Biology, G-quadruplex, 01 natural sciences, Biochemistry, Genetics and Molecular Biology (miscellaneous), RNA Transport, 03 medical and health sciences, Immune system, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Research Articles, 030304 developmental biology, 0303 health sciences, Messenger RNA, Ecology, 010405 organic chemistry, Repertoire, Repeat sequence, Biochemistry and Molecular Biology, RNA, RNA G-quadruplex structure, 0104 chemical sciences, G-Quadruplexes, Epstein-Barr Virus Nuclear Antigens, Gene Expression Regulation, RNA, Viral, DNA, Intergenic, Nucleolin, Biokemi och molekylärbiologi, Research Article
Abstract: This study demonstrates the dynamic and multifunctional aspects of RNA G4 structures., The role of G-quadruplex (G4) RNA structures is multifaceted and controversial. Here, we have used as a model the EBV-encoded EBNA1 and the Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded LANA1 mRNAs. We have compared the G4s in these two messages in terms of nucleolin binding, nuclear mRNA retention, and mRNA translation inhibition and their effects on immune evasion. The G4s in the EBNA1 message are clustered in one repeat sequence and the G4 ligand PhenDH2 prevents all G4-associated activities. The RNA G4s in the LANA1 message take part in similar multiple mRNA functions but are spread throughout the message. The different G4 activities depend on flanking coding and non-coding sequences and, interestingly, can be separated individually. Together, the results illustrate the multifunctional, dynamic and context-dependent nature of G4 RNAs and highlight the possibility to develop ligands targeting specific RNA G4 functions. The data also suggest a common multifunctional repertoire of viral G4 RNA activities for immune evasion.
Published: 2021

22. Consumption of ultra-processed foods associated with weight gain and obesity in adults: A multi-national cohort study

Author: Salvatore Panico, Vivian Viallon, José María Huerta, Heinz Freisling, Miguel Rodríguez-Barranco, Christopher Millett, Marc J. Gunter, Paolo Vineis, Christina C. Dahm, Giovanna Masala, Nasser Laouali, Elisabete Weiderpass, Verena Katzke, Charlotta Rylander, Lousie Brunkwall, Yvonne T. van der Schouw, Franziska Jannasch, Aurelio Barricarte, Fernanda Rauber, Carlos Augusto Monteiro, Jie Zhang, Jeroen W.G. Derksen, Paula Jakszyn, Geneviève Nicolas, Reynalda Cordova, Karl-Heinz Wagner, Renata Bertazzi Levy, Corinne Casagrande, Marie-Christine Boutron-Ruault, Francesca Mancini, Stina Ramne, Stina Bodén, Eszter P. Vamos, Guri Skeie, Anne Tjønneland, Jytte Halkjær, Aurora Perez-Cornago, Bernard Srour, Inge Huybrechts, Nathalie Kliemann, Sara Grioni, Matthias B. Schulze, Alicia K Heath, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Deutsches Krebsforschungszentrum, DKFZ, National Research Council, NRC, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C570/A16491, C8221/A19170, World Cancer Research Fund, WCRF, Institut National de la Santé et de la Recherche Médicale, Inserm, Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP: 2016/14302-7, Österreichischen Akademie der Wissenschaften, ÖAW, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Fondation de France: 00081166, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, School for Public Health Research, NIHR SPHR, The Public Health Policy Evaluation Unit is grateful for support from the NIHR School for Public Health Research . Swedish Cancer Society , Swedish Research Council and County Council of Västerbotten , Sweden., This work was partially financially supported by the Fondation de France (FDF, grant no. 00081166 , HF, RC)., Fernanda Rauber is a beneficiary of a postdoctoral fellowship from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) , grant numbers 2016/14302-7 ., The national cohorts are supported by the following funders: Ligue Contre le Cancer , Institut Gustave-Roussy , Mutuelle Générale de l'Education Nationale , Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid , German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health,Welfare and Sports (VWS) , Netherlands Cancer Registry (NKR) , LK Research Funds , Dutch Prevention Funds , Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS-ISCIII) , the Regional Governments of Andalucía , Asturias , Basque Country, Murcia , Navarra , and the Catalan Institute of Oncology (Barceloan), Spain), Cancer Research UK ( 14136 to EPIC-Norfolk, C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council ( 1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK)., Reynalda Cordova is a recipient of a DOC Fellowship of the Austrian Academy of Sciences at the Institute of Nutritional Sciences, University of Vienna.This work was partially financially supported by the Fondation de France (FDF, grant no. 00081166, HF, RC).Fernanda Rauber is a beneficiary of a postdoctoral fellowship from the Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo (FAPESP), grant numbers 2016/14302-7.The national cohorts are supported by the following funders: Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF) (Germany), Dutch Ministry of Public Health,Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland),World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS-ISCIII), the Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barceloan), Spain), Cancer Research UK (14136 to EPIC-Norfolk, and C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK).The Public Health Policy Evaluation Unit is grateful for support from the NIHR School for Public Health Research. Swedish Cancer Society, Swedish Research Council and County Council of V?sterbotten, Sweden.
Subjects: Male, NOVA, Food Handling, 030309 nutrition & dietetics, [SDV]Life Sciences [q-bio], Overweight, Critical Care and Intensive Care Medicine, DISEASE, Body Mass Index, 0302 clinical medicine, Risk Factors, Weight management, Prevalence, PARTICIPANTS, Poisson Distribution, Prospective Studies, 030212 general & internal medicine, 2. Zero hunger, RISK, 0303 health sciences, Nutrition and Dietetics, Middle Aged, CANCER, AGES, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, Multilevel Analysis, Female, medicine.symptom, Cohort study, Adult, DIET, 03 medical and health sciences, Ultra-processed foods, medicine, Humans, Adults, Obesity, VALIDITY, Weight gain, Aged, Nutrition & Dietetics, business.industry, medicine.disease, Diet, PRODUCTS, Relative risk, Linear Models, Fast Foods, 1111 Nutrition and Dietetics, business, Body mass index, Demography
Abstract: Background: There is a worldwide shift towards increased consumption of ultra-processed foods (UPF) with concurrent rising prevalence of obesity. We examined the relationship between the consumption of UPF and weight gain and risk of obesity. Methods: This prospective cohort included 348 748 men and women aged 25-70 years. Participants were recruited between 1992 and 2000 from 9 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Two body weight measures were available, at baseline and after a median follow-up time of 5 years. Foods and drinks were assessed at baseline by dietary questionnaires and classified according to their degree of processing using NOVA classification. Multilevel mixed linear regression was used to estimate the association between UPF consumption and body weight change (kg/5 years). To estimate the relative risk of becoming overweight or obese after 5 years we used Poisson regression stratified according to baseline body mass index (BMI). Results: After multivariable adjustment, higher UPF consumption (per 1 SD increment) was positively associated with weight gain (0.12 kg/5 years, 95% CI 0.09 to 0.15). Comparing highest vs. lowest quintile of UPF consumption was associated with a 15% greater risk (95% CI 1.11, 1.19) of becoming overweight or obese in normal weight participants, and with a 16% greater risk (95% CI 1.09, 1.23) of becoming obese in participants who were overweight at baseline. Conclusions: These results are supportive of public health campaigns to substitute UPF for less processed alternatives for obesity prevention and weight management. (c) 2021 Published by Elsevier Ltd.
Published: 2021

23. Leo1 is essential for the dynamic regulation of heterochromatin and gene expression during cellular quiescence

Author: Eriko Oya, Catherine Schurra, Ronit Weisman, Karl Ekwall, Mickaël Durand-Dubief, Adiel Cohen, Jun-ichi Nakayama, Vladimir Maksimov, Benoit Arcangioli, Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Karolinska Institutet [Stockholm], Open University of Israël, Dynamique du Génome - Dynamics of the genome, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), National Institute for Basic Biology [Okazaki] (NIBB), Graduate University for Advanced Studies [Hayama] (SOKENDAI), Work in the K.E. laboratory was supported by grants from the Swedish Cancer Society (C.F.) and the Swedish Research Council (V.R.). K.E. was the recipient of a Wenner-Gren stipend for a sabbatical stay at the Pasteur Institute, France. E.O. was the recipient of a postdoctoral fellowship and travel support from the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2704). Funding was provided by Cancerfonden, Vetenskapsrådet, Wenner-Gren Foundation and Japan Society for the Promotion of Science., We thank the BEA facility, particularly T. Damdimopoulos, for help in processing gene expression data., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: lcsh:QH426-470, Heterochromatin, [SDV]Life Sciences [q-bio], Biology, Resting Phase, Cell Cycle, Epigenesis, Genetic, Histones, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Gene Expression Regulation, Fungal, Gene expression, Schizosaccharomyces, Genetics, Reversible differentiation, Epigenetics, Molecular Biology, Gene, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Cellular quiescence, Research, Cell Cycle, Nuclear Proteins, RNA-Binding Proteins, Fission yeast, Chromatin, Cell biology, lcsh:Genetics, RNA Polymerase II, Schizosaccharomyces pombe Proteins, Paf1C, 030217 neurology & neurosurgery
Abstract: Background Cellular quiescence is a reversible differentiation state during which cells modify their gene expression program to inhibit metabolic functions and adapt to a new cellular environment. The epigenetic changes accompanying these alterations are not well understood. We used fission yeast cells as a model to study the regulation of quiescence. When these cells are starved for nitrogen, the cell cycle is arrested in G1, and the cells enter quiescence (G0). A gene regulatory program is initiated, including downregulation of thousands of genes—for example, those related to cell proliferation—and upregulation of specific genes—for example, autophagy genes—needed to adapt to the physiological challenge. These changes in gene expression are accompanied by a marked alteration of nuclear organization and chromatin structure. Results Here, we investigated the role of Leo1, a subunit of the conserved RNA polymerase-associated factor 1 (Paf1) complex, in the quiescence process using fission yeast as the model organism. Heterochromatic regions became very dynamic in fission yeast in G0 during nitrogen starvation. The reduction of heterochromatin in early G0 was correlated with reduced target of rapamycin complex 2 (TORC2) signaling. We demonstrated that cells lacking Leo1 show reduced survival in G0. In these cells, heterochromatic regions, including subtelomeres, were stabilized, and the expression of many genes, including membrane transport genes, was abrogated. TOR inhibition mimics the effect of nitrogen starvation, leading to the expression of subtelomeric genes, and this effect was suppressed by genetic deletion of leo1. Conclusions We identified a protein, Leo1, necessary for survival during quiescence. Leo1 is part of a conserved protein complex, Paf1C, linked to RNA polymerase II. We showed that Leo1, acting downstream of TOR, is crucial for the dynamic reorganization of chromosomes and the regulation of gene expression during cellular quiescence. Genes encoding membrane transporters are not expressed in quiescent leo1 mutant cells, and cells die after 2 weeks of nitrogen starvation. Taken together, our results suggest that Leo1 is essential for the dynamic regulation of heterochromatin and gene expression during cellular quiescence. Electronic supplementary material The online version of this article (10.1186/s13072-019-0292-7) contains supplementary material, which is available to authorized users.
Published: 2019

24. Nuclear processing of nascent transcripts determines synthesis of full-length proteins and antigenic peptides

Author: María José Lista, Marc Blondel, Laurence Malbert-Colas, Sébastien Apcher, Robin Fåhraeus, Marika Pla, Sarah Findakly, Chrysoula Daskalogianni, Rodrigo Prado Martins, Université Paris Diderot - Paris 7 (UPD7), Université de Bretagne Occidentale, University of Gdańsk (UG), Institut Gustave Roussy (IGR), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Umeå University, Institut National Du Cancer (INCa-10683), Inserm, Cancerfonden (160598), Vetenskapsradet, RECAMO (GACR P206/12/G151, MYES-NPS I-LO1413), Cancerforskningsfonden Norr, La Ligue contre le Cancer Grand-Ouest (CSIRGO)., Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, and Fåhraeus, Robin
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], [SDV.CAN]Life Sciences [q-bio]/Cancer, Major histocompatibility complex, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, MHC class I, RNA and RNA-protein complexes, Genetics, Humans, RNA, Messenger, Antigens, Immune Evasion, Cancer, 030304 developmental biology, Cell Nucleus, 0303 health sciences, biology, [SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT], Antigen processing, Histocompatibility Antigens Class I, Biochemistry and Molecular Biology, Intron, RNA, Translation (biology), interaction arn protéine, Nonsense Mediated mRNA Decay, Cell biology, G-Quadruplexes, Protein Biosynthesis, RNA splicing, biology.protein, Peptides, arn messager, régulation génique, nucléoline, Nucleolin, Biokemi och molekylärbiologi, 030217 neurology & neurosurgery, Autre (Sciences du Vivant)
Abstract: supplementary data online; International audience; Peptides presented on major histocompatibility (MHC) class I molecules form an essential part of the immune system's capacity to detect virus-infected or transformed cells. Earlier works have shown that pioneer translation peptides (PTPs) for the MHC class I pathway are as efficiently produced from introns as from exons, or from mRNAs targeted for the nonsense-mediated decay pathway. The production of PTPs is a target for viral immune evasion but the underlying molecular mechanisms that govern this non-canonical translation are unknown. Here, we have used different approaches to show how events taking place on the nascent transcript control the synthesis of PTPs and full-length proteins. By controlling the subcellular interaction between the G-quadruplex structure (G4) of a gly-ala encoding mRNA and nucleolin (NCL) and by interfering with mRNA maturation using multiple approaches, we demonstrate that antigenic peptides derive from a nuclear non-canonical translation event that is independently regulated from the synthesis of full-length proteins. Moreover, we show that G4 are exploited to control mRNA localization and translation by distinguishable mechanisms that are targets for viral immune evasion.
Published: 2019

25. The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor beta signaling

Author: Papoutsoglou, Panagiotis, Rodrigues Junior, Dorival Mendes, Morén, Anita, Bergman, Andrew, Pontén, Fredrik, Coulouarn, Cedric, Caja, Laia, Heldin, Carl-Henrik, Moustakas, Aristidis, Uppsala University, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Cancerfonden Swedish Cancer Society [CAN2012/438, CAN2015/438, CAN2018/469], Vetenskapsradet Swedish Research Council [K2013-66X-14936-10-5, 2017-01588-3, 2018-02757-3, 2015-02757, 2020-01291], Barncancerfonden [PR2018-0091], European Research Council European Research Council (ERC) European Commission [787472], Bodossaki Foundation, Alexander Onassis Foundation, Greece, Inserm Institut National de la Sante et de la Recherche Medicale (Inserm) European Commission, Universite de Rennes-1, ITMO Cancer AVIESAN Plan Cancer [C18007NS], Ludwig Cancer Research, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent
Subjects: Cancer och onkologi, [SDV.CAN]Life Sciences [q-bio]/Cancer, Oncogenes, Article, Transforming Growth Factor beta1, Autocrine Communication, MicroRNAs, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Neoplasms, Cancer and Oncology, Humans, Cell Proliferation, Signal Transduction, Cancer
Abstract: Activation of the transforming growth factor beta (TGF beta) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGF beta induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGF beta-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGF beta signaling, expression of TGF beta-target genes, and TGF beta-mediated cell cycle arrest. Moreover, MIR100HG silencing inhibited both normal and cancer cell motility and enhanced the cytotoxicity of cytostatic drugs. MIR100HG overexpression had an inverse impact on TGF beta signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGF beta 1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGF beta 1 cytokine secretion. In addition, TGF beta regulated let-7a-2-3p, miR-125b-5p, and miR-125b-1-3p expression, all encoded by MIR100HG intron-3. Certain intron-3 miRNAs may be involved in TGF beta/SMAD-mediated responses (let-7a-2-3p) and others (miR-100, miR-125b) in resistance to cytotoxic drugs mediated by MIR100HG. In support of a model whereby TGF beta induces MIR100HG, which then enhances TGF beta 1 secretion, analysis of human carcinomas showed that MIR100HG expression correlated with expression of TGFB1 and its downstream extracellular target TGFBI. Thus, MIR100HG controls the magnitude of TGF beta signaling via TGF beta 1 autoinduction and secretion in carcinomas.
Published: 2021

26. Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies

Author: Fulvio Ricceri, Joseph A. Rothwell, Amanda J. Cross, Graham G. Giles, Elisabete Weiderpass, Tilman Kühn, Emily Sonestedt, Yi Yang, Rudolf Kaaks, Valeria Pala, Anna Karakatsani, Dallas R. English, Rosario Tumino, Pilar Amiano, Antonia Trichopoulou, John L. Hopper, Leila Lujan-Barroso, Allison M. Hodge, Bengt Wallner, Ruth C. Travis, María Dolores López, Anne Tjønneland, Hazel M. Mitchell, Kostas Tsilidis, Domenico Palli, Harindra Jayasekara, Elio Riboli, Antonio Agudo, Robin Room, Heiner Boeing, Eva Ardanaz, Bas Bueno-de-Mesquita, Torkjel M. Sandanger, Pietro Ferrari, Robert J. MacInnis, Susana Merino, Andrew Haydon, Eleni Peppa, Marie-Christine Boutron-Ruault, Salvatore Panico, María José Sánchez, Marc J. Gunter, Hanna Sternby, Roger L. Milne, Gianluca Severi, Ana Lucia Mayen-Chacon, Centre international de Recherche sur le Cancer (CIRC), 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), VicHealth Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, CIRC Wellcome Trust, WT Medical Research Council, MRC: MC‐UU_12015/1, MR/M012190/1, MR/N003284/1 British Heart Foundation, BHF Department of Health and Social Care, DH Cancer Research UK, CRUK: C570/ A16491, C8221/A19170, C864/A14136 World Cancer Research Fund, WCRF Food Standards Agency, FSA Stroke Association European Commission, EC National Health and Medical Research Council, NHMRC: 1074383, 209057, 396414, GNT1163120 Cancer Council Victoria Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Stavros Niarchos Foundation, SNF Vetenskapsrådet, VR Consiglio Nazionale delle Ricerche, CNR Ministère des Affaires Sociales et de la Santé: GR‐IARC‐2003‐09‐12‐01 Instituto de Salud Carlos III, ISCIII Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Rijksinstituut voor Volksgezondheid en Milieu, RIVM Institut Gustave-Roussy Mutuelle Générale de l'Education Nationale, MGEN Ministry of Health and Social Solidarity, Greece Foundation for Alcohol Research and Education, FARE Hellenic Health Foundation, HHF, Australian National Health and Medical Research Council, Grant/Award Numbers: 1074383, 209057, 396414, GNT1163120, Cancer Council Victoria (Australia), Cancer Research UK, Grant/Award Numbers: C570/ A16491, C8221/A19170, C864/A14136, Catalan Institute of Oncology ‐ ICO (Spain), Danish Cancer Society, Deutsche Krebshilfe, the Deutsches Krebsforschungszentrum (Germany), Dutch Ministry of Public Health, Welfare and Sports, European Commission (Directorate General for Health and Consumer Affairs), Foundation for Alcohol Research and Education (Australia), French Ministry of Health, Grant/Award Number: Grant GR‐IARC‐2003‐09‐12‐01, Health Research Fund (FIS) ‐ Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Hellenic Health Foundation (Greece), Hellenic Ministry of Health and Social Solidarity (Greece), Institut National de la Santé et de la Recherche Médicale (France), Italian Association for Research on Cancer and the National Research Council (Italy), Ligue Contre le Cancer (France), LK Research Funds, Dutch Prevention Funds, the Dutch Zorg Onderzoek Nederland, Medical Research Council (UK), Grant/Award Numbers: MC‐UU_12015/1, MR/M012190/1, MR/N003284/1, Mutuelle Générale de l'Education Nationale, National Institute for Public Health and the Environment (RIVM) (the Netherlands), Netherlands Cancer Registry, Stavros Niarchos Foundation (Greece), Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust (UK), Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skåne (Sweden), the Federal Ministry of Education and Research (Germany), VicHealth (Australia), World Cancer Research Fund and Statistics Netherlands (the Netherlands), the Institut Gustave Roussy Funding information, We thank Carine Biessy and Bertrand Hemon for their technical contribution to EPIC data used in this work. We are also grateful to all the EPIC participants who have been part of the project, and to the many members of the study teams who enabled this research. We thank the original MCCS investigators and the diligent team, who recruited the participants and who continue working on follow‐up, for their contribution. We also express our gratitude to the many thousands of Melbourne residents who continue to participate in the study. This work was supported by the Direction Générale de la Santé (French Ministry of Health, Grant GR‐IARC‐2003‐09‐12‐01), by the European Commission (Directorate General for Health and Consumer Affairs) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark), the Ligue Contre le Cancer, the Institut Gustave Roussy, the Mutuelle Générale de l'Education Nationale and the Institut National de la Santé et de la Recherche Médicale (France), the Deutsche Krebshilfe, the Deutsches Krebsforschungszentrum and the Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity (Greece), the Italian Association for Research on Cancer and the National Research Council (Italy), the Dutch Ministry of Public Health, Welfare and Sports, the Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, the Dutch Zorg Onderzoek Nederland, the World Cancer Research Fund and Statistics Netherlands (the Netherlands), the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study, the Health Research Fund (FIS) ‐ Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology ‐ ICO (Spain), the Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skåne (Sweden), Cancer Research UK (C864/A14136 to EPIC‐Norfolk, C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (MR/N003284/1 and MC‐UU_12015/1 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford, United Kingdom), the Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust (UK). MCCS cohort recruitment was funded by Cancer Council Victoria ( https://www.cancervic.org.au/ ) and VicHealth ( https://www.vichealth.vic.gov.au/ ). The MCCS was further supported by Australian National Health and Medical Research Council (NHMRC) ( https://www.nhmrc.gov.au/ ) grants 209057, 396414 and 1074383, and ongoing follow‐up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Harindra Jayasekara is supported by NHMRC grant GNT1163120. John L. Hopper is a NHMRC Senior Principal Research Fellow. Yi Yang is supported by a Melbourne Research Scholarship from the University of Melbourne. Robin Room's position was funded by the Foundation for Alcohol Research and Education. The sponsors had no role in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and and decision to submit the manuscript for publication.
Subjects: Male, Cancer Research, Gastroenterology, 0302 clinical medicine, Prospective Studies, Stomach cancer, Prospective cohort study, stomach cancer, biology, Stomach, Incidence, Hazard ratio, Smoking, cardia cancer, Cardia cancer, Middle Aged, Lifetime alcohol intake, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, medicine.anatomical_structure, Oncology, Drinking of alcoholic beverages, 030220 oncology & carcinogenesis, Consum d'alcohol, Female, Life Sciences & Biomedicine, Cohort study, Adult, medicine.medical_specialty, Alcohol Drinking, [SDV.CAN]Life Sciences [q-bio]/Cancer, Helicobacter Infections, noncardia cancer, 03 medical and health sciences, Stomach Neoplasms, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Aged, Science & Technology, Helicobacter pylori, EPIC, lifetime alcohol intake, MCCS, business.industry, Càncer d'estómac, Kirurgi, Australia, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Noncardia cancer, medicine.disease, biology.organism_classification, Surgery, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (Phomogeneity = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences., National Health and Medical Research Council of Australia 1074383 209057 396414 GNT1163120, Canadian Institutes of Health Research (CIHR) Cancer Council Victoria, Cancer Research UK C570/A16491 C8221/A19170 C864/A14136, Catalan Institute of Oncology - ICO (Spain), Danish Cancer Society, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (Germany), Dutch Ministry of Public Health, Welfare and Sports, European Commission European Commission Joint Research Centre, Foundation for Alcohol Research and Education (Australia), French Ministry of Health GR-IARC-2003-09-12-01, Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII), Junta de Andalucía, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Hellenic Health Foundation (Greece), Hellenic Ministry of Health and Social Solidarity (Greece), Institut National de la Sante et de la Recherche Medicale (Inserm), Consiglio Nazionale delle Ricerche (CNR), Associazione Italiana per la Ricerca sul Cancro (AIRC), Ligue Contre le Cancer (France), LK Research Funds, Dutch Prevention Funds, Netherlands Organization for Scientific Research (NWO), UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MC-UU_12015/1 MR/M012190/1 MR/N003284/, Mutuelle Generale de l'Education Nationale, National Institute for Public Health and the Environment (RIVM) (the Netherlands), Netherlands Cancer Registry, Stavros Niarchos Foundation (Greece), Stroke Association (UK), British Heart Foundation, Department of Health (UK), Food Standards Agency (UK), Wellcome Trust, Swedish Cancer Society, Swedish Scientific Council (Sweden), Regional Government of Skane (Sweden), Federal Ministry of Education & Research (BMBF), VicHealth (Australia), World Cancer Research Fund and Statistics Netherlands (the Netherlands), Institut Gustave Roussy
Published: 2021

27. Inflammatory potential of the diet and risk of breast cancer in the European Investigation into Cancer and Nutrition (EPIC) study

Author: Verena Katzke, Anne M. May, Carlota Castro-Espin, Paula Jakszyn, Christina C. Dahm, Elisabete Weiderpass, Matthias B. Schulze, Guri Skeie, María José Sánchez, Catalina Bonet, Maria Dolores Chirlaque, Sanam Shah, Nasser Laouali, Dagfinn Aune, José Ramón Quirós, Sabina Sieri, Eva Ardanaz, Salvatore Panico, Gianluca Severi, Carlotta Sacerdote, Antonio Agudo, Stina Bodén, Melissa A. Merritt, Iger T Gram, Rosario Tumino, Krasimira Aleksandrova, Giovanna Masala, Elio Riboli, Renée Turzanski-Fortner, Pilar Amiano, Anne Tjønneland, Laure Dossus, Manon Cairat, 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), Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII: PI15/00639, European Social Fund, ESF, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Rijksinstituut voor Volksgezondheid en Milieu, RIVM, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, European Regional Development Fund, ERDF: FI19/00197, NIHR Imperial Biomedical Research Centre, BRC, This work was funded by Instituto de Salud Carlos III through the project PI15/00639 (Co-funded by European Regional Development Fund [ERDF], a way to build Europe). C. Castro-Espin was funded by Instituto de Salud Carlos III through the Grant FI19/00197 (Co-funded by European Social Fund. ESF investing in your future). The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). The funders of this study had no role in the decisions about the analysis or interpretation of the data, or preparation, review or approval of the manuscript., and We thank CERCA Programme/Generalitat de Catalunya for institutional support. We also thank the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands, for their contribution and ongoing support to the EPIC Study.
Subjects: Adult, medicine.medical_specialty, Epidemiology, Nutritional Status, Breast Neoplasms, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, 030212 general & internal medicine, Inflammatory potential of the diet, Prospective study, Prospective cohort study, Life Style, Inflammation, 2. Zero hunger, business.industry, Proportional hazards model, Hazard ratio, Chronic inflammation, Middle Aged, medicine.disease, Obesity, Diet, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Cohort, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Body mass index
Abstract: International audience; The role of chronic inflammation on breast cancer (BC) risk remains unclear beyond as an underlying mechanism of obesity and physical activity. We aimed to evaluate the association between the inflammatory potential of the diet and risk of BC overall, according to menopausal status and tumour subtypes. Within the European Prospective Investigation into Cancer and Nutrition cohort, 318,686 women were followed for 14 years, among whom 13,246 incident BC cases were identified. The inflammatory potential of the diet was characterized by an inflammatory score of the diet (ISD). Multivariable Cox regression models were used to assess the potential effect of the ISD on BC risk by means of hazard ratios (HR) and 95% confidence intervals (CI). ISD was positively associated with BC risk. Each increase of one standard deviation (1-Sd) of the score increased by 4% the risk of BC (HR = 1.04; 95% CI 1.01–1.07). Women in the highest quintile of the ISD (indicating a most pro-inflammatory diet) had a 12% increase in risk compared with those in the lowest quintile (HR = 1.12; 95% CI 1.04–1.21) with a significant trend. The association was strongest among premenopausal women, with an 8% increased risk for 1-Sd increase in the score (HR = 1.08; 95% CI 1.01–1.14). The pattern of the association was quite homogeneous by BC subtypes based on hormone receptor status. There were no significant interactions between ISD and body mass index, physical activity, or alcohol consumption. Women consuming more pro-inflammatory diets as measured by ISD are at increased risk for BC, especially premenopausal women.
Published: 2021

28. Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort

Author: Joseph A. Rothwell, Giovanna Masala, José María Huerta, Aurora Perez-Cornago, Elisabete Weiderpass, Anja Olsen, Magritt Brustad, Claudia Agnoli, Corinne Casagrande, Guri Skeie, Ulrika Ericson, Verena Katzke, Mazda Jenab, Christina C. Dahm, Anne Tjønneland, Geneviève Nicolas, Rudolf Kaaks, Inge Huybrechts, Veronika Fedirko, Carlotta Sacerdote, Neil Murphy, Maria Wennberg, Veronique Chajes, Jeroen W.G. Derksen, Matthias B. Schulze, Elom K. Aglago, Bas Bueno-de-Mesquita, Alicia K Heath, Pilar Amiano, Salvatore Panico, Paula Jakszyn, Rosario Tumino, Marc J. Gunter, Inger T. Gram, María José Sánchez, 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), 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, 1000143, MR/M012190/1, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, National Research Council, NRC, University of Maryland School of Public Health, SPH, Cancer Research UK, CRUK: 14136, C8221/A29017, World Cancer Research Fund, WCRF, Imperial College London, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Rijksinstituut voor Volksgezondheid en Milieu, RIVM, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, World Cancer Research Fund, Grant/Award Number: WCRF 2013/1002 Funding information trans, The authors would like to thank the EPIC study participants and staff for their valuable contribution to this research. The authors would also like to thank Ms Beatrice Vozar, Mr Bertrand Hemon and Ms Carine Biessy for the analysis of plasma samples, and the preparation of the databases. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology—ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC‐Norfolk, C8221/A29017 to EPIC‐Oxford), MedicalResearch Council (1000143 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford). (United Kingdom), the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. The EPIC‐Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC‐PC_13048 and MC‐UU_12015/1). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors would like to acknowledge the use of data and samples from EPIC centres in Cambridge, France, Asturias, and Navarro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Our study was funded by a grant from the World Cancer Research Fund to Marc Gunter (Grant number: WCRF 2013/1002)., Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Health Research Fund (FIS)?Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology?ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), MedicalResearch Council (1000143 to EPIC-Norfolk, and MR/M012190/1 to EPIC-Oxford). (United Kingdom), the National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1, MC-PC_13048 and MC-UU_12015/1). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. The authors would like to acknowledge the use of data and samples from EPIC centres in Cambridge, France, Asturias, and Navarro. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Our study was funded by a grant from the World Cancer Research Fund to Marc Gunter (Grant number: WCRF 2013/1002).
Subjects: Cancer Research, medicine.medical_specialty, Colorectal cancer, Myristic acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, Gastroenterology, fatty acids, DISEASE, Palmitic acid, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, COLON, medicine, 2 SIDES, 2. Zero hunger, chemistry.chemical_classification, business.industry, Fatty acid, Odds ratio, ASSOCIATION, medicine.disease, Elaidic acid, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Oncology, chemistry, 030220 oncology & carcinogenesis, biomarker, Stearic acid, business, dietary intake, LIPIDS
Abstract: International audience; Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial-processed trans (iTFA), and ruminant-sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow-up = 15 years). In a nested case-control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable-adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 = 0.80; 95%CI:0.69-0.92), myristic acid (HRQ5vsQ1 = 0.83, 95%CI:0.74-0.93) and palmitic acid (HRQ5vsQ1 = 0.81, 95%CI:0.70-0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR1-SD = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR1-SD = 1.04, 95%CI:0.95-1.15, Pheterogeneity = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1-SD = 1.07, 95%CI:1.02-1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.
Published: 2021

29. Impact of IL-1β and the IL-1R antagonist on relapse risk and survival in AML patients undergoing immunotherapy for remission maintenance

Author: Karin Christenson, Hanna Grauers Wiktorin, Fredrik B. Thorén, Nuttida Issdisai, Ebru Aydin, Kristoffer Hellstrand, Anna Martner, University of Gothenburg (GU), Meda Pharma, Bad Homburg, Germany (Re: Mission Study Sponsor), the Swedish Cancer Society (Cancerfonden, Grant no. 19 0033 Pj, 19 0449 Pj, 19 0030 SIA, CAN 2018/582), the Swedish Research Council (Grant no. 2020-01437, 2020-02783), the Swedish Society for Medical Research (SSMF), the Swedish State via the ALF agreement (Grant no. ALFGBG-724881, and ALFFGBG-724861), and the Sahlgrenska Academy at University of Gothenburg
Subjects: Oncology, medicine.medical_specialty, nox2, Myeloid, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], il-1β, Immunology, Interleukin-1beta, relapse preventive immunotherapy, acute myeloid leukemia, Relapse prevention, 03 medical and health sciences, 0302 clinical medicine, il-2, Recurrence, Internal medicine, medicine, Immunology and Allergy, Humans, Progenitor cell, RC254-282, 030304 developmental biology, Original Research, 0303 health sciences, business.industry, Antagonist, Myeloid leukemia, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunotherapy, RC581-607, Receptor antagonist, histamine, 3. Good health, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Cytokine, il-1ra, Interleukin-2, Immunologic diseases. Allergy, business, 030215 immunology, Research Article
Abstract: International audience; Interleukin-1 beta (IL-1β), a pro-inflammatory cytokine, has been ascribed a role in the expansion of myeloid progenitors in acute myeloid leukemia (AML) and in promoting myeloid cell-induced suppression of lymphocyte-mediated immunity against malignant cells. This study aimed at defining the potential impact of IL-1β in the post-remission phase of AML patients receiving immunotherapy for relapse prevention in an international phase IV trial of 84 patients (ClinicalTrials.gov; NCT01347996). Consecutive serum samples were collected from AML patients in first complete remission (CR) who received cycles of relapse-preventive immunotherapy with histamine dihydrochloride (HDC) and lowdose interleukin-2 (IL-2). Low IL-1β serum levels before and after the first HDC/IL-2 treatment cycle favorably prognosticated leukemia-free survival and overall survival. Serum levels of IL-1β were significantly reduced in patients receiving HDC/IL-2. HDC also reduced the formation of IL-1β from activated human PBMCs in vitro. Additionally, high serum levels of the IL-1 receptor antagonist IL-1RA were associated with favorable outcome, and AML patients with low IL-1β along with high IL-1RA levels were strikingly protected against leukemic relapse. Our results suggest that strategies to target IL-1β might impact on relapse risk and survival in AML.
Published: 2021

30. A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC

Author: Ingegerd Johansson, David S. Lopez, Alicia K Heath, Amanda J. Cross, Anne Tjønneland, J. Ramón Quirós, Melissa A. Merritt, Paula Jakszyn, Bas Bueno-de-Mesquita, Pilar Amiano, Anne Kirstine Eriksen, Manuela M. Bergmann, Marc J. Gunter, Bernard Srour, David C. Muller, Piet A. van den Brandt, Matthias B. Schulze, Salvatore Panico, Claudia Agnoli, Pietro Ferrari, Marco Lukic, José María Huerta, Christina C. Dahm, Therese Haugdahl Nøst, Areti Papadopoulou, Aurelio Barricarte Gurrea, Rosario Tumino, María José Sánchez, Fulvio Ricceri, Nadia Bastide, Paolo Vineis, Ulrika Ericson, Eva Ardanaz, Gianluca Severi, Guri Skeie, Aurora Perez-Cornago, Nikos Papadimitriou, Emmanouil Bouras, Elisabete Weiderpass, Ellio Riboli, Ioanna Tzoulaki, Heiner Boeing, Stina Bodén, Giovanna Masala, Jeroen W.G. Derksen, Jonna Berntsson, Verena Katzke, Elena Critselis, Konstantinos K. Tsilidis, University of Ioannina, Maastricht University [Maastricht], Imperial College London, Biomedical Research Foundation of the Academy of Athens (BRFAA), International Agency for Cancer Research (IACR), German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), 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, University of Hawai'i [Honolulu] (UH), The University of Texas Health Science Center at Houston (UTHealth), University of Oxford [Oxford], University of Potsdam, The Arctic University of Norway (UiT), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Umeå University, Università degli studi di Torino = University of Turin (UNITO), Lund University [Lund], Instituto de Salud Carlos III [Madrid] (ISC), Aarhus University [Aarhus], IRCCS Istituto Nazionale dei Tumori [Milano], University of Copenhagen = Københavns Universitet (KU), National Institute for Public Health and the Environment [Bilthoven] (RIVM), University of Naples Federico II, La Salle [Ramon Llull University], Utrecht University [Utrecht], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, International Council of Ophthalmology, ICO, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C8221/A29017, World Cancer Research Fund, WCRF: WCRF 2014/1180, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, Funding This work was supported by the World Cancer Research Fund International Regular Grant Programme (WCRF 2014/1180 to Konstantinos K. Tsilidis). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the National Institute for Health Research Imperial Biomedical Research Centre. The national cohorts are supported by the Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)?Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (ICO) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), and Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization., Funding This work was supported by the World Cancer Research Fund International Regular Grant Programme ( WCRF 2014/1180 to Konstantinos K. Tsilidis). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the National Institute for Health Research Imperial Biomedical Research Centre . The national cohorts are supported by the Danish Cancer Society (Denmark), Ligue Contre le Cancer , Institut Gustave Roussy , Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid , German Cancer Research Center ( DKFZ ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research ( BMBF ) (Germany), Dutch Ministry of Public Health , Welfare and Sports ( VWS ), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund ( WCRF ), Statistics Netherlands (The Netherlands), Health Research Fund (FIS)– Instituto de Salud Carlos III ( ISCIII ), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology ( ICO ) (Spain), Swedish Cancer Society , Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Epidemiologie, and RS: GROW - R1 - Prevention
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Riboflavin, colorectal cancer, Lower risk, Cohort Studies, Animal science, beta-Carotene, Risk Factors, Epidemiology, medicine, cohort study, Humans, Prospective Studies, Hepatology, Gastroenterology & Hepatology, business.industry, Hazard ratio, Gastroenterology, food and beverages, 1103 Clinical Sciences, Confidence interval, European Prospective Investigation into Cancer and Nutrition, Diet, epidemiology, nutrition, business, Colorectal Neoplasms, Cohort study
Abstract: Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04–1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04–1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93–0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90–0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90–0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92–0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93–0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.
Published: 2020

31. Presence of tumor-infiltrating CD8+ T cells and macrophages correlates to longer overall survival in patients undergoing isolated hepatic perfusion for uveal melanoma liver metastasis

Author: Roger Olofsson Bagge, Junko Johansson, Peter Naredi, Jan Siarov, Roberta Kiffin, Per Lindnér, Anna Martner, Jan Mattsson, Johan Mölne, University of Gothenburg (GU), Sahlgrenska University Hospital [Gothenburg], Cancerfonden [CAN 2016/351 19 0033 Pj], Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden, The Agreement for Medical Education and Research [ALFGBG-724881], Stiftelsen Assar Gabrielssons Fond [FB18-15], and Vetenskapsrådet [2016-01928]
Subjects: CD68+, Isolated hepatic perfusion, CD14, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, T cells, 03 medical and health sciences, 0302 clinical medicine, Immune system, Uveal melanoma, medicine, Immunology and Allergy, Cytotoxic T cell, RC254-282, business.industry, Melanoma, isolated hepatic perfusion, FOXP3, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunosuppression, RC581-607, medicine.disease, CD8+, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Cancer research, Immunologic diseases. Allergy, business, CD8, 030215 immunology
Abstract: International audience; Uveal melanoma is a malignant tumor of the eye that often metastasizes to the liver conferring poor prognosis. When comparing immune profiles in peripheral blood of untreated patients with uveal melanoma liver metastasis and healthy blood donors, it was observed that immune cells of uveal melanoma patients carried immunosuppressive features. Patient blood contained an increased content of CD14+HLA-DR−/low M-MDSCs and inflammatory CD16+ monocytes, while their dendritic cells expressed lower levels of activation markers. Melanoma patients also harbored an enhanced fraction of CD4+Foxp3+ regulatory T cells, while their effector T cells expressed lower levels of the activation marker HLA-DR. Biopsies from liver metastases were obtained from patients with uveal melanoma that subsequently underwent hyperthermic isolated hepatic perfusion (IHP) with melphalan. There were trends indicating a positive correlation between a high infiltration of CD8+ T cells in metastases and an activated immune cell profile in blood. High metastatic infiltration of CD8+ T cells and CD68+ macrophages, but not of immunosuppressive CD163+ macrophages, correlated to a longer overall survival in patients treated with IHP. Hence, while the immune system of patients with uveal melanoma shows signs of immunosuppression, the presence of activated immune cells may correlate to a longer survival, at least following IHP treatment.
Published: 2020

32. Association between anthropometry and lifestyle factors and risk of B cell lymphoma: an exposome wide analysis

Author: Anne Tjønneland, Claudia Agnoli, Pietro Ferrari, Pilar Amiano, Bas Bueno-de-Mesquita, Miguel Rodríguez-Barranco, Alexandra Nieters, Aurelio Barricarte, Roel Vermeulen, Elisabete Weiderpass, Giovanna Masala, José María Huerta, Marta Solans, Delphine Casabonne, Federico Canzian, Caroline Besson, Florentin Späth, Gianluca Severi, Carlotta Sacerdote, James McKay, Catalina Bonet, Sabine Naudin, Fatemeh Saberi Hosnijeh, Sofia Christakoudi, Heinz Freisling, Rosario Tumino, Kristin Benjaminsen Borch, Rudolf Kaaks, Matthias B. Schulze, Yolanda Benavente, Anja Olsen, Charlotta Rylander, Anika Knuppel, Marie Christine Boutron Ruault, Mats Jerkeman, Immunology, Centre international de Recherche sur le Cancer (CIRC), Institut Gustave Roussy (IGR), 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, Mode de vie, génétique et santé : études intégratives et transgénérationnelles (U1018 (Équipe 9)), Institut Gustave Roussy (IGR)-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-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, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 179 2017SGR1085 Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, CIRC Wellcome Trust, WT: 205212/Z/16/Z National Research Council, NRC Medical Research Council, MRC: MR/M012190/1 Cancer Research UK, CRUK: 14136, C570/A11692, C570/A16491 World Cancer Research Fund, WCRF European Commission, EC Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF: 01EO1303 Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Agència de Gestió d'Ajuts Universitaris i de Recerca, AGAUR Ligue Contre le Cancer Vetenskapsrådet, VR NordForsk Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Institut Gustave-Roussy Mutuelle Générale de l'Education Nationale, MGEN European Regional Development Fund, ERDF: ERC2009‐AdG 232997, PI13/00061, PI13/01162, PI14/01219, PI17/01280 Hellenic Health Foundation, HHF, Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR), CERCA Programme/Generalitat de Catalunya for institutional support, Grant/Award Number: 2017SGR1085, Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy and National Research Council (Italy), Cancer Research UK, Grant/Award Numbers: 14136 (to EPIC‐Norfolk), C570/A11692, C570/A16491, Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), (Spain), Danish Cancer Society (Denmark), TRANSCAN/Dutch Cancer Society, Grant/Award Number: 179, NOVEL consortium, Dutch Ministry of Public Health, Welfare and Sports (VWS), Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), European Commission (DG‐SANCO), Federal Ministry of Education and Research (BMBF), German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research, Grant/Award Number: BMBF 01EO1303, German Institute of Human Nutrition Potsdam‐Rehbruecke, Nuthetal (Germany), Institut Gustave Roussy, Institut National de la Sante et de la Recherche Medicale (France), International Agency for Research on Cancer, Ligue Natinale Contre le Cancer, LK Research Funds, Medical Research Council, Grant/Award Numbers: 1000143 (to EPIC‐Norfolk), MR/M012190/1 (to EPIC‐Oxford), Mutuelle Generale de l'Education Nationale, Netherlands Cancer Registry (NKR), Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Spanish Ministry of Economy and Competitiveness ‐ Carlos III Institute of Health cofunded by FEDER funds/European Regional Develpment Fund (ERDF) ‐ a way to build Europe, Grant/Award Numbers: PI13/00061 (to Granada), PI13/01162 (to EPIC‐Murcia), PI17/01280, PI14/01219 (to Barcelona), Statistics Netherlands (The Netherlands), Grant/Award Number: Grant number: ERC2009‐AdG 232997, Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Vasterbotten (Sweden), the Hellenic Health Foundation (Greece), Wellcome Trust, Grant/Award Number: 205212/Z/16/Z, and World Cancer Research Fund (WCRF) Funding information
Subjects: Oncology, Male, Limfomes, Cancer Research, Lymphoma, Follicular lymphoma, Cohort Studies, 0302 clinical medicine, Risk Factors, Prospective Studies, Càncer, Prospective cohort study, B-cell lymphoma, Cancer, 2. Zero hunger, wide association study, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Anthropometry, exposome wide association study, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Plasma cell neoplasm, Middle Aged, exposome‐, CANCER, 3. Good health, European Prospective Investigation into Cancer and Nutrition, exposome&#8208, MEDITERRANEAN DIET, 030220 oncology & carcinogenesis, OBESITY, Lymphomas, Female, SMOKING, NON-HODGKIN-LYMPHOMA, Life Sciences & Biomedicine, Cancer Epidemiology, prospective study, NATIONAL-HEALTH, medicine.medical_specialty, Inverse Association, lifestyle, Lymphoma, B-Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, lymphoma, exposome‐wide association study, exposome, DIETARY-FAT, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, VALIDITY, Life Style, Cancer och onkologi, Science & Technology, Proportional hazards model, business.industry, medicine.disease, exposome-wide association study, PHYSICAL-ACTIVITY, PROSPECTIVE COHORT, Cancer and Oncology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business
Abstract: To better understand the role of individual and lifestyle factors in human disease, an exposome‐wide association study was performed to investigate within a single‐study anthropometry measures and lifestyle factors previously associated with B‐cell lymphoma (BCL). Within the European Prospective Investigation into Cancer and nutrition study, 2402 incident BCL cases were diagnosed from 475 426 participants that were followed‐up on average 14 years. Standard and penalized Cox regression models as well as principal component analysis (PCA) were used to evaluate 84 exposures in relation to BCL risk. Standard and penalized Cox regression models showed a positive association between anthropometric measures and BCL and multiple myeloma/plasma cell neoplasm (MM). The penalized Cox models additionally showed the association between several exposures from categories of physical activity, smoking status, medical history, socioeconomic position, diet and BCL and/or the subtypes. PCAs confirmed the individual associations but also showed additional observations. The PC5 including anthropometry, was positively associated with BCL, diffuse large B‐cell lymphoma (DLBCL) and MM. There was a significant positive association between consumption of sugar and confectionary (PC11) and follicular lymphoma risk, and an inverse association between fish and shellfish and Vitamin D (PC15) and DLBCL risk. The PC1 including features of the Mediterranean diet and diet with lower inflammatory score showed an inverse association with BCL risk, while the PC7, including dairy, was positively associated with BCL and DLBCL risk. Physical activity (PC10) was positively associated with DLBCL risk among women. This study provided informative insights on the etiology of BCL., What's new? The “exposome” includes all non‐genetic exposures (e.g. diet, viral, environmental, etc.), with the goal of understanding how those exposures may affect an individual's health. In this study, the authors used a technique called “EWAS” (exposome‐wide association study) to identify multiple factors that are associated with B‐cell lymphoma (BCL) risk. Their results confirm both previously reported risk factors and protective factors. In addition, they identify several previously unknown associations. These new insights, gained via the analysis of multiple exposures, suggest that traditional single‐factor approaches may be suboptimal compared with an EWAS approach.
Published: 2020

33. EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity

Author: Maike Frye, Simon Stritt, Henrik Ortsäter, Magda Hernandez Vasquez, Mika Kaakinen, Andres Vicente, John Wiseman, Lauri Eklund, Jorge L Martínez-Torrecuadrada, Dietmar Vestweber, Taija Mäkinen, Swedish Cancer Society (Cancerfonden), Knut and Alice Wallenberg Foundation, Swedish Research Council, Unión Europea. Comisión Europea. H2020, Deutsche Forschungsgemeinschaft (Alemania), European Molecular Biology Organization, Comunidad de Madrid (España), Swedish Cancer Society, Knut & Alice Wallenberg Foundation, H2020 European Research Council, German Research Foundation (DFG), and European Molecular Biology Organization (EMBO)
Subjects: Mouse, QH301-705.5, Cell- och molekylärbiologi, Science, Receptor, EphB4, lymphatic endothelium, Ephrin-B2, Mice, Homeostasis, Animals, Claudin-5, Biology (General), Lymphatic Vessels, Endothelial Cells, Cell Biology, cell-cell junction, ephrin, Intercellular Junctions, Medicine, Cell and Molecular Biology, Gene Deletion, Research Article, Developmental Biology, Signal Transduction
Abstract: Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function., eLife digest Lymph vessels are thin walled tubes that, similar to blood vessels, carry white blood cells, fluids and waste. Unlike veins and arteries, however, lymph vessels do not carry red blood cells and their main function is to remove excess fluid from tissues. The cells that line vessels in the body are called endothelial cells, and they are tightly linked together by proteins to control what goes into and comes out of the vessels. The chemical, physical and mechanical signals that control the junctions between endothelial cells are often the same in different vessel types, but their effects can vary. The endothelial cells of both blood and lymph vessels have two interacting proteins on their membrane known as EphrinB2 and its receptor, EphB4. When these two proteins interact, the EphB4 receptor becomes activated, which leads to changes in the junctions that link endothelial cells together. Frye et al. examined the role of EphrinB2 and EphB4 in the lymphatic system of mice. When either EphrinB2 or EphB4 are genetically removed in newborn or adult mice, lymph vessels become disrupted, but no significant effect is observed on blood vessels. The reason for the different responses in blood and lymph vessels is unknown. The results further showed that lymphatic endothelial cells need EphB4 and EphrinB2 to be constantly interacting to maintain the integrity of the lymph vessels. Further examination of human endothelial cells grown in the laboratory revealed that this constant signalling controls the internal protein scaffold that determines a cell’s shape and integrity. Changes in the internal scaffold affect the organization of the junctions that link neighboring lymphatic endothelial cells together. The loss of signalling between EphrinB2 and EphB4 in lymph vessels reflects the increase in vessel leakage seen in response to bacterial infections and in some genetic conditions such as lymphoedema. Finding ways to control the signalling between these two proteins could help treat these conditions by developing drugs that improve endothelial cell integrity in lymph vessels.
Published: 2020

34. Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study

Author: Fulvio Ricceri, Tilman Kühn, Marc J. Gunter, Guri Skeie, Roel Vermeulen, Sabina Sieri, Elio Riboli, Aurora Perez-Cornago, Heather Ward, Amanda J. Cross, Verena Katzke, José María Huerta, Manuela M. Bergmann, Konstantinos K. Tsilidis, Yahya Mahamat-Saleh, Eva Ardanaz, Antonia Trichopoulou, Salvatore Panico, Elisabete Weiderpass, Cecilie Kyrø, Rosario Tumino, Antonio Agudo, María José Sánchez, Alexandra Vulcan, Valerie Cayssials, Giovanna Masala, Pilar Amiano, Dorthe Nyvang, Genevieve Buckland, Paula Jakszyn, Eleni Peppa, Mazda Jenab, Bodil Ohlsson, Marie-Christine Boutron-Ruault, Anne Tjønneland, Anna Karakatsani, Heiner Boeing, Franck Carbonnel, Christina C. Dahm, Cristina Lasheras, 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), 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), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Ministerie van Volksgezondheid, Welzijn en Sport, VWS Deutsche Krebshilfe Cancer Research UK, CRUK: C8221/A19170, 14136 VetenskapsrÃ¥det, VR Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer German Cancer Research Center, DKFZ Bundesministerium fÃ¼r Bildung und Forschung, BMBF Bundesministerium fÃ¼r Bildung und Frauen, BMBF Institut National de la SantÃ© et de la Recherche MÃ©dicale, Inserm KrÃ¦ftens BekÃ¦mpelse, DCS Instituto de Salud Carlos III, ISCIII: PI15/00639 German Cancer Research Center, DKFZ National Research Council, NRC 6236 Generalitat de Catalunya European Commission, EC European Regional Development Fund, FEDER Centre International de Recherche sur le Cancer, CIRC RD06/0020 Deutsche Krebshilfe German Cancer Research Center, DKFZ PI13/01162, PI13/00061 Cancerfonden World Cancer Research Fund, WCRF: ERC-2009-AdG 232997 NordForsk Associazione Italiana per la Ricerca sul Cancro, AIRC Medical Research Council, MRC: MR/M012190/1 European Regional Development Fund, FEDER, Our study has been funded by Instituto de Salud Carlos III through the project PI15/00639 (Co-funded by European Regional Development Fund [ERDF], a way to build Europe). We thank CERCA Programme/Generalitat de Catalunya for institutional support. Regional Government of Asturias, German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM, France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020, Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 to EPICNorfolk, and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPICNorfolk, MR/M012190/1 to EPIC-Oxford, United Kingdom).
Subjects: Oncology, Male, Cancer Research, Colorectal cancer, Cohort Studies, 0302 clinical medicine, MARKERS, Risk Factors, ATHEROSCLEROSIS MAASTRICHT CODAM, Prospective Studies, LOW-GRADE INFLAMMATION, Prospective cohort study, INDEX, Abdominal obesity, biology, Hazard ratio, GLUCOSE-METABOLISM, Middle Aged, C-REACTIVE PROTEIN, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, inflammatory potential of the diet, 030220 oncology & carcinogenesis, Cohort, Adenocarcinoma, Regression Analysis, Female, epidemiology, medicine.symptom, Colorectal Neoplasms, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, prospective cohort, [SDV.CAN]Life Sciences [q-bio]/Cancer, colorectal cancer, MECHANISMS, Association, 03 medical and health sciences, COLON, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Obesity, Exercise, Inflammation, Science & Technology, business.industry, association, C-reactive protein, Feeding Behavior, medicine.disease, digestive system diseases, Diet, PHYSICAL-ACTIVITY, Nutrition Assessment, Multivariate Analysis, biology.protein, business
Abstract: Pro-inflammatory diets are associated with risk of developing colorectal cancer (CRC), however inconsistencies exist in subsite- and sex-specific associations. The relationship between CRC and combined lifestyle-related factors that contribute towards a low-grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed-up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumours). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More pro- inflammatory diets were related to a higher CRC risk, particularly for colon cancer; Hazar Ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval (CI) 1.04-1.27) for CRC, 1.24 (95% CI 1.09-1.41) for colon cancer and 0.99 (95% CI 0.83-1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS were 1.62 (95% CI 1.31- 2.01) for colon cancer overall and 2.11 (95% CI 1.50-2.97) for colon cancer in men. This study shows that more pro-inflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men. This article is protected by copyright. All rights reserved.
Published: 2020

35. Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author: Sanikini, Harinakshi, Muller, David C, Sophiea, Marisa, Rinaldi, Sabina, Agudo, Antonio, Duell, Eric J, Weiderpass, Elisabete, Overvad, Kim, Tjønneland, Anne, Halkjaer, Jytte, Boutron-Ruault, Marie-Christine, Carbonnel, Franck, Cervenka, Iris, Boeing, Heiner, Kaaks, Rudolf, Kühn, Tilman, Trichopoulou, Antonia, Martimianaki, Georgia, Karakatsani, Anna, Pala, Valeria, Palli, Domenico, Mattiello, Amalia, Tumino, Rosario, Sacerdote, Carlotta, Skeie, Guri, Rylander, Charlotta, López, María Dolores Chirlaque, Sánchez, Maria-Jose, Ardanaz, Eva, Regnér, Sara, Stocks, Tanja, Bueno-de-Mesquita, Bas, Vermeulen, Roel C H, Aune, Dagfinn, Tong, Tammy Y N, Kliemann, Nathalie, Murphy, Neil, Chadeau-Hyam, Marc, Gunter, Marc J, Cross, Amanda J, Cancer Research UK, Department of Medical and Clinical Genetics, University of Helsinki, 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), 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), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre international de Recherche sur le Cancer (CIRC), 6236, PI13/00061, PI13/01162 Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, IARC Stand Up To Cancer, SU2C National Research Council, NRC Medical Research Council, MRC: 1000143, MR/M012190/1 Cancer Research UK, CRUK: 14136, C570/A16491, C8221/A19170 World Cancer Research Fund, WCRF European Commission, EC Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Vetenskapsrådet, VR Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Fondation Gustave Roussy Hellenic Health Foundation, HHF, This research was funded by the Stand Up to Cancer campaign for Cancer Research UK. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM, France), German Cancer Aid, German Cancer Research Centre (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), National Institute for Public Health and the Environment (Bilthoven, The Netherlands) for their contribution to data collection, Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia (no. 6236) and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 to KTK, NJW, and C570/A16491 to RCT and C8221/A19170 to TK [EPIC-Oxford]), Medical Research Council (1000143 to KTK, NJW, MR/M012190/1 to TK [EPIC-Oxford, United Kingdom]).
Subjects: Male, obesity, Esophageal Neoplasms, 3122 Cancers, [SDV.CAN]Life Sciences [q-bio]/Cancer, gastric, Europe/epidemiology, Cohort Studies, Stomach Neoplasms/classification, SDG 3 - Good Health and Well-being, Stomach Neoplasms, esophageal, Risk Factors, cancer, Body Fat Distribution, Humans, VDP::Medisinske Fag: 700, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, Càncer, Nutrició, Reproductive History, Nutrition, Proportional Hazards Models, reproductive, hormones, Anthropometry, Middle Aged, VDP::Medical disciplines: 700, Europe, Esophageal Neoplasms/classification, Female, Cancer Epidemiology
Abstract: Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow‐up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m2: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist‐to‐hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. 98 vs. 0.82 vs. 84 vs. 2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs., What's new? Obesity can change the body's hormone balance, and encourage the onset of cancer. Here, the authors investigated the relationship between obesity, hormones, and esophageal and gastric cancers. Using data from the EPIC cohort, they obtained information about anthropometric and reproductive factors for 476,160 participants. Excess fat around the waist, they found, was associated with esophageal adenocarcinoma and gastric cardia cancer, in women and men. In women, bearing children, as well as younger age at first pregnancy, had an inverse association with certain cancers. Ovariectomy was positively associated with gastric non‐cardia cancer, suggesting involvement of hormone pathways in these malignancies.
Published: 2020

36. Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort

Author: Patrick Arveux, Elio Riboli, Carla H. van Gils, Marina Kvaskoff, Rudolf Kaaks, María José Sánchez, Kim Overvad, Pilar Amiano, Naomi E. Allen, Elisabete Weiderpass, Christina C. Dahm, Catalina Bonet, Carlo La Vecchia, Giovanna Masala, Amalia Mattiello, José Ramón Quirós, Manuela M. Bergmann, Matthias B. Schulze, Marc J. Gunter, Anna Karakatsani, Daniel Ángel Rodríguez-Palacios, Vivian Viallon, Valeria Pala, Ruth C. Travis, Renée T. Fortner, Fulvio Ricceri, Rosario Tumino, Antonia Trichopoulou, Evelyn M. Monninkhof, Anne Tjønneland, Laure Dossus, Agnès Fournier, Aurelio Barricarte Gurrea, Anika Hüsing, 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, Cancer Research Foundation in Northern Sweden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Deutsche Krebshilfe Cancer Research UK, CRUK: C8221/A19170, C570/A16491 Vetenskapsrådet, VR Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer German Cancer Research Center, DKFZ Bundesministerium für Bildung und Forschung, BMBF Bundesministerium für Bildung und Forschung, BMBF Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Associazione Italiana per la Ricerca sul Cancro, AIRC National Research Council, NRC Mutuelle Générale de l'Education Nationale, MGEN Hellenic Health Foundation, HHF Institut National de la Santé et de la Recherche Médicale, Inserm Fondation Gustave Roussy European Commission, EC Centre International de Recherche sur le Cancer, IARC RD06/0020 German Cancer Research Center, DKFZ Deutsche Krebshilfe Cancerfonden World Cancer Research Fund, WCRF: ERC‐2009‐AdG 232997 PI13/01162, PI13/00061 NordForsk Medical Research Council, MRC: MR/M012190/1, The coordination of EPIC is financially supported by the European Commission (DG‐SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), ERC‐2009‐AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC‐Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten, The Cancer Research Foundation of Northern Sweden (Sweden), Cancer Research UK (C570/A16491 and C8221/A19170), Medical Research Council (MR/M012190/1) (EPIC‐Oxford, and United Kingdom). 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). We are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php .
Subjects: Cancer Research, primary prevention, Overweight, Body Mass Index, COLORECTAL-CANCER, Cohort Studies, 0302 clinical medicine, Endometrial cancer, Medicine, risk factors, endometrial cancer, 2. Zero hunger, Framingham Risk Score, Incidence, Incidence (epidemiology), Middle Aged, 3. Good health, Europe, Menopause, Oncology, 030220 oncology & carcinogenesis, Cohort, Female, NUTRITION, medicine.symptom, Cancer Epidemiology, Adult, Pes corporal, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), BREAST, OVARIAN-CANCER, 03 medical and health sciences, Humans, Risk factor, Hormone therapy, Aged, Models, Statistical, business.industry, ORAL-CONTRACEPTIVE USE, Body weight, medicine.disease, Endometrial Neoplasms, Càncer d'endometri, business, Body mass index, Hormonoteràpia, Contraceptives, Oral, Demography
Abstract: Endometrial cancer (EC) incidence rates vary ~10‐fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low‐risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow‐up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m2), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m2) and HT use (to all non‐HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks., What's new? Endometrial cancer rates vary considerably around the world, with incidence rates higher in Europe and North America than in parts of Asia and Africa. Here, the authors investigated how much of the risk disparity arises from modifiable factors, and how much modifying these factors could reduce cancer incidence. The 10% of European women with lowest risk had similar incidence to women in low‐risk countries, they found. Their model predicted that in European women, maintaining BMI below 23 kg/m2 and avoiding postmenopausal hormone use could reduce risk by 30%. Long‐term use of oral contraceptives could reduce risk by 42.5%.
Published: 2020

37. Consumption of Fish and Long-chain n-3 Polyunsaturated Fatty Acids Is Associated With Reduced Risk of Colorectal Cancer in a Large European Cohort

Author: Magritt Brustad, Veronika Fedirko, Marc J. Gunter, Anja Olsen, Antonia Trichopoulou, Geneviève Nicolas, Anna Karakatsani, Veronique Chajes, Gianluca Severi, Elom K. Aglago, Eva Ardanaz, Aurora Perez-Cornago, Kim Overvad, Cristina Lasheras, Salvatore Panico, Verena Katzke, Bas Bueno-de-Mesquita, José María Huerta, Neil Murphy, Christina C. Dahm, Maria Wennberg, Teresa Norat, Bodil Ohlsson, Elisabete Weiderpass, Antonio Agudo, Heather Ward, Anne Tjønneland, Valeria Pala, Tilman Kühn, Bethany Van Guelpen, Guri Skeie, Rosario Tumino, María José Sánchez, A. M. May, Corinne Casagrande, Jeroen W.G. Derksen, Marie-Christine Boutron-Ruault, Elio Riboli, Agnès Fournier, Sophie Hellstrand, Inge Huybrechts, Georgia Martimianaki, Alessio Naccarati, Tobias Pischon, Amanda J. Cross, Pilar Amiano, Domenico Palli, Centre de recherche en épidémiologie et santé des populations (CESP), 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), RD06/0020 6236 Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, CIRC Wellcome Trust, WT: C570/A16491, C8221/A19170, MR/M012190/1 National Research Council, NRC Medical Research Council, MRC British Heart Foundation, BHF Cancer Research UK, CRUK World Cancer Research Fund, WCRF: WCRF 2013/1002 Food Standards Agency, FSA Stroke Association European Commission, EC Institut National de la Santé et de la Recherche Médicale, Inserm Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer Stavros Niarchos Foundation, SNF Instituto de Salud Carlos III, ISCIII Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Associazione Iblea per la Ricerca Epidemiologica, AIRE Institut Gustave-Roussy Mutuelle Générale de l'Education Nationale, MGEN Ministry of Health and Social Solidarity, Greece Fondation Gustave Roussy Hellenic Health Foundation, HHF, Funding Supported by a grant from the World Cancer Research Fund ( WCRF ) to Marc Gunter (grant number: WCRF 2013/1002 ). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer . The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer , Institut Gustave Roussy , Mutuelle Générale de l'Education Nationale , and Institut National de la Santé et de la Recherche Médicale ( INSERM ) (France), German Cancer Aid , German Cancer Research Center ( DKFZ ), and Federal Ministry of Education and Research ( BMBF ) (Germany), Hellenic Health Foundation , Stavros Niarchos Foundation , and the Hellenic Ministry of Health and Social Solidarity (Greece), Italian Association for Research on Cancer ( AIRC ), National Research Council , and Associazione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS) Ragusa, Associazione Volontari Italiani Sangu ( AVIS ) Ragusa, Sicilian Government (Italy), Dutch Ministry of Public Health , Welfare and Sports ( VWS ), Netherlands Cancer Registry ( NKR ), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund ( WCRF ), and Statistics Netherlands (the Netherlands), Nordic Center of Excellence Programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), Regional Governments of Andalucía , Asturias, Basque Country, Murcia (No. 6236) and Navarra, and the Centro de Investigación Biomédica en Red en Epidemiología y Salud Pública and Instituto de Salud Carlos II ( ISCIII RETIC) ( RD06/0020 ) (Spain), Swedish Cancer Society , Swedish Scientific Council , and Regional Government of Skåne and Västerbotten (Sweden), Cancer Research UK , Medical Research Council , Stroke Association , British Heart Foundation , Department of Health , Food Standards Agency , the Wellcome Trust (UK), Cancer Research UK ( 14136 to EPIC-Norfolk, C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council ( 1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom)., Funding Supported by a grant from the World Cancer Research Fund (WCRF) to Marc Gunter (grant number: WCRF 2013/1002). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, and Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), and Federal Ministry of Education and Research (BMBF) (Germany), Hellenic Health Foundation, Stavros Niarchos Foundation, and the Hellenic Ministry of Health and Social Solidarity (Greece), Italian Association for Research on Cancer (AIRC), National Research Council, and Associazione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS) Ragusa, Associazione Volontari Italiani Sangu (AVIS) Ragusa, Sicilian Government (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands), Health Research Fund (FIS), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia (No. 6236) and Navarra, and the Centro de Investigaci?n Biom?dica en Red en Epidemiolog?a y Salud P?blica and Instituto de Salud Carlos II (ISCIII RETIC) (RD06/0020) (Spain), Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Sk?ne and V?sterbotten (Sweden), Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, the Wellcome Trust (UK), Cancer Research UK (14136 to EPIC-Norfolk, and C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom).
Subjects: Colorectal cancer, [SDV]Life Sciences [q-bio], Àcids grassos insaturats, Physiology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Càncer colorectal, Fatty Acids, Omega-3, Medicine, Animals, Humans, Prospective Studies, 2. Zero hunger, chemistry.chemical_classification, Unsaturated fatty acids, Epidemiologic, Gastroenterology & Hepatology, Hepatology, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, business.industry, Gastroenterology, Fishes, 1103 Clinical Sciences, Odds ratio, medicine.disease, Eicosapentaenoic acid, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Diet, chemistry, Seafood, Docosahexaenoic acid, 030220 oncology & carcinogenesis, Omega 3, Cohort, Colonic Neoplasms, Tumorigenesis, 030211 gastroenterology & hepatology, Docosapentaenoic acid, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Polyunsaturated fatty acid
Abstract: Background & Aims There is an unclear association between intake of fish and long-chain n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) and colorectal cancer (CRC). We examined the association between fish consumption, dietary and circulating levels of n-3 LC-PUFAs, and ratio of n-6:n-3 LC-PUFA with CRC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods Dietary intake of fish (total, fatty/oily, lean/white) and n-3 LC-PUFA were estimated by food frequency questionnaires given to 521,324 participants in the EPIC study; among these, 6291 individuals developed CRC (median follow up, 14.9 years). Levels of phospholipid LC-PUFA were measured by gas chromatography in plasma samples from a sub-group of 461 CRC cases and 461 matched individuals without CRC (controls). Multivariable Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs), respectively, with 95% CIs. Results Total intake of fish (HR for quintile 5 vs 1, 0.88; 95% CI, 0.80–0.96; Ptrend = .005), fatty fish (HR for quintile 5 vs 1, 0.90; 95% CI, 0.82–0.98; Ptrend = .009), and lean fish (HR for quintile 5 vs 1, 0.91; 95% CI, 0.83–1.00; Ptrend = .016) were inversely associated with CRC incidence. Intake of total n-3 LC-PUFA (HR for quintile 5 vs 1, 0.86; 95% CI, 0.78–0.95; Ptrend = .010) was also associated with reduced risk of CRC, whereas dietary ratio of n-6:n-3 LC-PUFA was associated with increased risk of CRC (HR for quintile 5 vs 1, 1.31; 95% CI, 1.18–1.45; Ptrend < .001). Plasma levels of phospholipid n-3 LC-PUFA was not associated with overall CRC risk, but an inverse trend was observed for proximal compared with distal colon cancer (Pheterogeneity = .026). Conclusions In an analysis of dietary patterns of participants in the EPIC study, we found regular consumption of fish, at recommended levels, to be associated with a lower risk of CRC, possibly through exposure to n-3 LC-PUFA. Levels of n-3 LC-PUFA in plasma were not associated with CRC risk, but there may be differences in risk at different regions of the colon.
Published: 2020

38. Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations:a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Author: Harms, L.M., Scalbert, A., Zamora-Ros, R., Rinaldi, S., Jenab, M., Murphy, N., Achaintre, D., Tjønneland, A., Olsen, A., Overvad, K., Romana Mancini, F., Mahamat-Saleh, Y., Boutron-Ruault, M.-C., Kühn, T., Katzke, V., Trichopoulou, A., Martimianaki, G., Karakatsani, A., Palli, D., Panico, S., Sieri, S., Tumino, R., Sacerdote, C., Bueno-De-Mesquita, B., Vermeulen, R.C.H., Weiderpass, E., Nøst, T.H., Lasheras, C., Rodríguez-Barranco, M., Huerta, J.M., Barricarte, A., Dorronsoro, M., Hultdin, J., Gunter, M., Riboli, E., Aleksandrova, K., IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, Centre de recherche en épidémiologie et santé des populations (CESP), 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), PI13/00061, PI13/01162 RD06/0020 6236 KrÃ¦ftens BekÃ¦mpelse, DCS Deutsches Krebsforschungszentrum, DKFZ Centre International de Recherche sur le Cancer, CIRC College of Environmental Science and Forestry, State University of New York, ESF National Research Council, NRC Medical Research Council, MRC: CP15/00100, MR/M012190/1 Cancer Research UK, CRUK: C8221/A19170 World Cancer Research Fund, WCRF: ERC-2009-AdG 232997 European Commission, EC Institut National de la SantÃ© et de la Recherche MÃ©dicale, Inserm Bundesministerium fÃ¼r Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Ligue Contre le Cancer VetenskapsrÃ¥det, VR Instituto de Salud Carlos III, ISCIII NordForsk European Social Fund, ESF Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe Mutuelle GÃ©nÃ©rale de l'Education Nationale, MGEN, The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale and Institut National de la Santé et de la Recherche Médicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC (RD06/0020) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). R. Z.-R. is supported by the ‘Miguel Servet’ programme (CP15/00100) from the Institute of Health Carlos III and the European Social Fund (ESF).
Subjects: Male, 0301 basic medicine, Medicine (miscellaneous), Gastroenterology, Cohort Studies, chronic diseases, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Neoplasms, Caffeic acid, Medicine, Malalties cròniques, odds ratio, Prospective Studies, Prospective cohort study, Nutrition and Dietetics, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, biology, food and beverages, Full Papers, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Näringslära, Europe, hormone replacement therapy, Polifenols, Cohort, Female, standard deviation, Human and Clinical Nutrition, Cohort study, Adult, Plasma measurements, medicine.medical_specialty, 030209 endocrinology & metabolism, body mass index, Diet Surveys, C-reactive protein, 03 medical and health sciences, Internal medicine, Humans, polyphenols, Aged, Inflammation, 030109 nutrition & dietetics, business.industry, Daidzein, Polyphenols, Diet, cardiovascular diseases, Cross-Sectional Studies, Nutrition Assessment, chemistry, confidence interval, Polyphenol, plasma measurements, inflammation, Chronic diseases, randomized controlled trial, biology.protein, high-sensitivity C-reactive protein, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Biomarkers
Abstract: Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 % CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 % CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 % CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 % CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 % CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 % CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.
Published: 2020

39. Predicted basal metabolic rate and cancer risk in the European Prospective Investigation into Cancer and Nutrition

Author: Elisabete Weiderpass, Kim Overvad, Giovanna Masala, Guy Fagherazzi, Rudolf Kaaks, Daniel Redondo-Sánchez, Sabina Rinaldi, Ulrica Ericson, Dagfinn Aune, Pilar Amiano, Therese Haugdahl Nøst, Antonia Trichopoulou, Rosario Tumino, Paula Jakszyn, Neil Murphy, Elio Riboli, Tilman Kühn, Francesca Mancini, Heinz Freisling, Bas Bueno-de-Mesquita, Marie-Christine Boutron-Ruault, Maria Santucci de Magistris, Inge Huybrechts, Marc J. Gunter, Carlotta Sacerdote, Nathalie Kliemann, Christina C. Dahm, Vivian Viallon, Vittorio Krogh, Lena Maria Nilsson, Isabel Drake, Anne M. May, Heiner Boeing, Matthias B. Schulze, Carlo La Vecchia, Anne Tjønneland, Anna Karakatsani, Aurelio Barricarte Gurrea, Konstantinos K. Tsilidis, María Dolores Chirlaque, José Ramón Quirós, Centre international de Recherche sur le Cancer (CIRC), Université de Paris-Saclay [Villejuif], 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, Deutsche Krebshilfe Cancer Research UK, CRUK: C8221/A19170, 14136, C570/A16491 Ligue Contre le Cancer Bundesministerium für Bildung und Forschung, BMBF Bundesministerium für Bildung und Forschung, BMBF Institut National de la Santé et de la Recherche Médicale, Inserm Kræftens Bekæmpelse, DCS Research Councils UK, RCUK Health and Medical Research Fund, HMRF: FIS Zorginstituut Nederland, ZIN PI13/01162, PI13/00061 World Cancer Research Fund, WCRF: ERC‐2009‐AdG 232997 Associazione Italiana per la Ricerca sul Cancro, AIRC National Research Council, NRC Ecumenical Project for International Cooperation, EPIC Institut National de la Santé et de la Recherche Médicale, Inserm European Commission, EU Centre International de Recherche sur le Cancer, CIRC Norway Deutsches Krebsforschungszentrum, DKFZ: DKFZ World Cancer Research Fund, WCRF Cancerfonden NordForsk Medical Research Council, MRC: MR/M012190/1, 1000143, The authors would like to thank the EPIC study participants and staff for their valuable contribution to this research. The authors would also like to thank Mr Bertrand Hemon for his support in preparing the databases and Dr Joseph Rothwell for his support in creating the figures. The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM, France), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF, Germany), the Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro‐AIRC‐Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), ERC‐2009‐AdG 232997 and Nordforsk, Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway), Health Research Fund (FIS) of the Spanish Ministry of Health (FIS, PI13/00061 to Granada, PI13/01162 to EPIC‐Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC‐Norfolk, C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (1000143 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford, and United Kingdom).
Subjects: Oncology, Adult, Male, metabolic disorder, Cancer Research, medicine.medical_specialty, obesity, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Neoplasms, medicine, Humans, cancer, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, Risk factor, Càncer, Nutrició, Aged, Cancer, Nutrition, Sex Characteristics, business.industry, Incidence (epidemiology), Incidence, Hazard ratio, Metabolic disorder, Middle Aged, medicine.disease, Obesity, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, Nutrition Assessment, 030220 oncology & carcinogenesis, Basal metabolic rate, basal metabolic rate, Female, Basal Metabolism, business
Abstract: Emerging evidence suggests that a metabolic profile associated with obesity may be a more relevant risk factor for some cancers than adiposity per se. Basal metabolic rate (BMR) is an indicator of overall body metabolism and may be a proxy for the impact of a specific metabolic profile on cancer risk. Therefore, we investigated the association of predicted BMR with incidence of 13 obesity-related cancers in the European Prospective Investigation into Cancer and Nutrition (EPIC). BMR at baseline was calculated using the WHO/FAO/UNU equations and the relationships between BMR and cancer risk were investigated using multivariable Cox proportional hazards regression models. A total of 141,295 men and 317,613 women, with a mean follow-up of 14 years were included in the analysis. Overall, higher BMR was associated with a greater risk for most cancers that have been linked with obesity. However, among normal weight participants, higher BMR was associated with elevated risks of esophageal adenocarcinoma (hazard ratio per 1-standard deviation change in BMR [HR 1-SD]: 2.46; 95% CI 1.20; 5.03) and distal colon cancer (HR 1-SD: 1.33; 95% CI 1.001; 1.77) among men and with proximal colon (HR 1-SD: 1.16; 95% CI 1.01; 1.35), pancreatic (HR 1-SD: 1.37; 95% CI 1.13; 1.66), thyroid (HR 1-SD: 1.65; 95% CI 1.33; 2.05), postmenopausal breast (HR 1-SD: 1.17; 95% CI 1.11; 1.22) and endometrial (HR 1-SD: 1.20; 95% CI 1.03; 1.40) cancers in women. These results indicate that higher BMR may be an indicator of a metabolic phenotype associated with risk of certain cancer types, and may be a useful predictor of cancer risk independent of body fatness.
Published: 2020

40. Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: A multinational cohort study

Author: Manuela M. Bergmann, Elio Riboli, Christina C. Dahm, Marc J. Gunter, Christina Bamia, David C. Muller, Pauline Bazelle, Antonio Agudo, Isabelle Romieu, Heather Ward, Pietro Ferrari, Patrick Arveux, Anja Olsen, Tammy Y.N. Tong, Elin Thysell, Julie A. Schmidt, María José Sánchez, Adam S. Butterworth, Aurelio Barricarte Gurrea, Peter Nilsson, Pilar Amiano, Kim Overvad, Fulvio Ricceri, Rosario Tumino, Salvatore Panico, Michael J. Sweeting, Evelyn M. Monninkhof, Anne Tjønneland, Marina Kvaskoff, Vincenzo Bagnardi, Olov Rolandsson, Konstantinos K. Tsilidis, Mazda Jenab, H. Susan J. Picavet, Paolo Vineis, Tilman Kühn, Heinz Freisling, Gianluca Severi, John Danesh, Claudia Agnoli, Hannah Lennon, Marije F. Bakker, Vivian Viallon, Virginia Menéndez, Rudolf Kaaks, Nicholas J. Wareham, Heiner Boeing, Carmen Santiuste, Jonas Manjer, Elisabete Weiderpass, Domenico Palli, Ioanna Tzoulaki, Cristian Ricci, Centre de recherche en épidémiologie et santé des populations (CESP), 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), 2018-1-PL SHS-06-CIRC-1 LSHM_CT_2006_037197 HEALTH24 F2-2012-279233 PI13/00061, PI13/01162 2018-123 RD06/0020 G0800270, MR/ L003120/1 Kræftens Bekæmpelse, DCS German Cancer Research Center, DKFZ Centre International de Recherche sur le Cancer, IARC National Research Council, NRC Medical Research Council, MRC: MR/M012190/1 British Heart Foundation, BHF: 26 RG/08/014, RG13/ 13/30194, SP/09/002 Cancer Research UK, CRUK: C570/A16491, C8221/A19170 World Cancer Research Fund, WCRF European Commission, EC European Research Council, ERC: 268834 Bundesministerium für Bildung und Forschung, BMBF Cancerfonden Ministerie van Volksgezondheid, Welzijn en Sport, VWS Vetenskapsrådet, VR Ministère des Affaires Sociales et de la Santé: GR-IARC-2003-09-12-01 Direction Générale de la Compétitivité, de l’Industrie et des Services, DGCIS Associazione Italiana per la Ricerca sul Cancro, AIRC Deutsche Krebshilfe, This work was supported by the Direction Générale de la Santé (French Ministry of Health) (Grant GR-IARC-2003-09-12-01) and by the French National Cancer Institute (INCA_N°2018-123), and the Cancéropôle Ile-de-France (N°2018-1-PL SHS-06-CIRC-1). Funding for the InterAct project was provided by the EU FP6 programme (grant no. LSHM_CT_2006_037197). EPIC-CVD has been supported by the European Union Framework 7 (HEALTH24 F2-2012-279233), the European Research Council (268834), the UK Medical Research 25 Council (G0800270 and MR/ L003120/1), the British Heart Foundation (SP/09/002 and 26 RG/08/014 and RG13/ 13/30194), and the UK National Institute of Health Research. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark), German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report., Butterworth, Adam [0000-0002-6915-9015], Danesh, John [0000-0003-1158-6791], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Cancer Research UK, Freisling, H, Viallon, V, Lennon, H, Bagnardi, V, Ricci, C, Butterworth, A, Sweeting, M, Muller, D, Romieu, I, Bazelle, P, Kvaskoff, M, Arveux, P, Severi, G, Bamia, C, Kuhn, T, Kaaks, R, Bergmann, M, Boeing, H, Tjonneland, A, Olsen, A, Overvad, K, Dahm, C, Menendez, V, Agudo, A, Sanchez, M, Amiano, P, Santiuste, C, Gurrea, A, Tong, T, Schmidt, J, Tzoulaki, I, Tsilidis, K, Ward, H, Palli, D, Agnoli, C, Tumino, R, Ricceri, F, Panico, S, Picavet, H, Bakker, M, Monninkhof, E, Nilsson, P, Manjer, J, Rolandsson, O, Thysell, E, Weiderpass, E, Jenab, M, Riboli, E, Vineis, P, Danesh, J, Wareham, N, Gunter, M, Ferrari, P, 29790514 - Ricci, Cristian, Overvad, Kim [0000-0001-6429-7921], Dahm, Christina C [0000-0003-0481-2893], and Tong, Tammy Y N [0000-0002-0284-8959]
Subjects: Male, lcsh:Medicine, Disease, Diabete, Body Mass Index, Cohort Studies, 0302 clinical medicine, Risk Factors, Neoplasms, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Càncer, 11 Medical and Health Sciences, Cancer, 2. Zero hunger, Medicine(all), Incidence, Hazard ratio, Diabetes, General Medicine, Middle Aged, Cardiovascular disease, 3. Good health, Cardiovascular diseases, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Obesitat, Female, Type 2, Cohort study, Research Article, Adult, Alcohol Drinking, Cancer and cardiometabolic multimorbidity, Healthy lifestyle, Obesity, Prevention, Diabetes Mellitus, Type 2, Humans, Proportional Hazards Models, Risk Reduction Behavior, Life Style, Multimorbidity, 03 medical and health sciences, Environmental health, General & Internal Medicine, medicine, Journal Article, Diabetes Mellitus, Cancer och onkologi, business.industry, Proportional hazards model, Malalties cardiovasculars, lcsh:R, medicine.disease, Cancer and Oncology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Body mass index
Abstract: Background Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. Methods In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. Results During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. Conclusion Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.
Published: 2020

41. Prospective analysis of circulating metabolites and endometrial cancer risk

Author: Alicia K Heath, Eirini Kouloura, Pilar Amiano, Joseph A. Rothwell, Marta Crous-Bou, Konstantinos K. Tsilidis, Melissa A. Merritt, Julie A. Schmidt, Lucie Lécuyer, María José Sánchez, Rosario Tumino, Domenico Palli, Hector C. Keun, Marc J. Gunter, Roel Vermeulen, Matthias B. Schulze, Inger T. Gram, Laure Dossus, Amalia Mattiello, Aurelio Barricarte Gurrea, Sandra Colorado-Yohar, Therese Haugdahl Nøst, Ruth C. Travis, Gianluca Severi, Carlotta Sacerdote, Claudia Agnoli, Naomi E. Allen, Elisabete Weiderpass, Alexandros P. Siskos, Carine Biessy, Vivian Viallon, Renée T. Fortner, Rudolf Kaaks, Niki Dimou, Sofia Christakoudi, Sabina Rinaldi, Sub Inorganic Chemistry and Catalysis, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, International Agency for Cancer Research (IACR), Imperial College London, European Food Safety Authority (EFSA), University of Hawai'i [Honolulu] (UH), Nuffield Department of Population Health [Oxford], University of Oxford [Oxford], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University Hospital of North Norway [Tromsø] (UNN), 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, University of Potsdam, Harvard T.H. Chan School of Public Health, University of Granada [Granada], CIBER de Epidemiología y Salud Pública (CIBERESP), Institute for Cancer Research, Prevention and Clinical Network (ISPRO), IRCCS Istituto Nazionale dei Tumori [Milano], Provincial Health Authority (ASP 7) [Ragusa, Italy], University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II, Utrecht University [Utrecht], Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, Academy of Pharmaceutical Sciences, APS, National Research Council, NRC, Imperial Experimental Cancer Medicine Centre, ECMC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MR/M012190/1, Cancer Research UK, CRUK: C19335/A21351, C8221/ A29017, World Cancer Research Fund, WCRF, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, NIHR Imperial Biomedical Research Centre, BRC, This work was supported by Cancer Research UK (CRUK) (grant number C19335/A21351, to MJG and HK).The metabolomics infrastructure in the Division of Cancer, Imperial College London is supported by the Imperial College Experimental Cancer Medicine Centre, the Imperial College Cancer Research UK Centre and the NIHR Imperial Biomedical Research Centre (APS & HK). The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, Institut National de la Sant? et de la Recherche M?dicale (INSERM) (France), German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Sk?ne and V?sterbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford). (United Kingdom)., The metabolomics infrastructure in the Division of Cancer, Imperial College London is supported by the Imperial College Experimental Cancer Medicine Centre , the Imperial College Cancer Research UK Centre and the NIHR Imperial Biomedical Research Centre (APS & HK). The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics , School of Public Health , Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC) . The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer , Institut Gustave Roussy , Mutuelle Générale de l'Education Nationale , Institut National de la Santé et de la Recherche Médicale (INSERM) (France), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds , Dutch Prevention Funds , Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF) , Statistics Netherlands (The Netherlands), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) , Regional Governments of Andalucía, Asturias , Basque Country, Murcia and Navarra , and the Catalan Institute of Oncology - ICO (Spain), Swedish Cancer Society , Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK ( 14136 to EPIC-Norfolk, C8221/ A29017 to EPIC-Oxford), Medical Research Council ( 1000143 to EPIC-Norfolk, This work was supported by Cancer Research UK (CRUK) (grant number C19335/A21351 , to MJG and HK)., University of Oxford, University of Naples Federico II = Università degli studi di Napoli Federico II, Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, Universidad de Granada = University of Granada (UGR), University of Potsdam = Universität Potsdam, HAL UVSQ, Équipe, Cancer Research UK, and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: 0301 basic medicine, Trastorns del metabolisme, [SDV]Life Sciences [q-bio], BMI, body mass index, NIST, National Institute of Standards and Technology, Body Mass Index, Serine, 0302 clinical medicine, Endometrial cancer, Risk Factors, WC, waist circumference, LC-MS/MS, liquid chromatography-tandem mass spectrometry, Prospective Studies, 2. Zero hunger, SPHINGOMYELIN, Endometrial Neoplasms/blood, Sphingomyelins/blood, Obstetrics & Gynecology, Obstetrics and Gynecology, C0, free carnitine, Middle Aged, Lipids, MHT, menopausal hormone therapy, AMINO-ACID, Sphingomyelins, 3. Good health, European Prospective Investigation into Cancer and Nutrition, [SDV] Life Sciences [q-bio], Disorders of metabolism, Oncology, 030220 oncology & carcinogenesis, Obesitat, Amino acids, Tumor/blood, NUTRITION, Female, ULOQ, upper limit of quantification, Life Sciences & Biomedicine, medicine.medical_specialty, Carnitine/blood, medicine.drug_class, MODELS, Glycine, LLOQ, lower limit of quantification, Glycine/blood, Malignancy, Article, 03 medical and health sciences, Carnitine, Internal medicine, Biomarkers, Tumor, medicine, Humans, Metabolomics, 1112 Oncology and Carcinogenesis, Serine/blood, Oncology & Carcinogenesis, Obesity, Aged, SRM, standard reference material, Science & Technology, LOD, limit of detection, SM, sphingomyelin, EPIC, European Prospective Investigation into Cancer and Nutrition, business.industry, IARC, International Agency for Research on Cancer, PROFILES, Odds ratio, medicine.disease, SYNTHASES, Sphingolipid, Endometrial Neoplasms, BODY-MASS INDEX, CI, confidence interval, OR, odds ratio, 030104 developmental biology, Endocrinology, Càncer d'endometri, Estrogen, Biomarkers, Tumor/blood, Case-Control Studies, 1114 Paediatrics and Reproductive Medicine, SD, standard deviation, business, CVs, coefficients of variation, Body mass index, Biomarkers
Abstract: This work was supported by Cancer Research UK (CRUK) (grant number C19335/A21351, to MJG and HK) . The metabolomics infrastructure in the Division of Cancer, Imperial College London is supported by the Imperial College Experimental Can-cer Medicine Centre, the This work was supported by Cancer Research UK (CRUK) (grant number C19335/A21351, to MJG and HK) . The metabolomics infrastructure in the Division of Cancer, Imperial College London is supported by the Imperial College Experimental Can-cer Medicine Centre, the Imperial College Cancer Research UK Centre and the NIHR Imperial Biomedical Research Centre (APS & HK) . The co-ordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Im-perial Biomedical Research Centre (BRC) . The national cohorts are sup-ported by: Danish Cancer Society (Denmark) ; Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France) ; German Cancer Aid, German Cancer Research Center (DKFZ) , German Institute of Human Nutrition PotsdamRehbruecke (DIfE) , Federal Ministry of Education and Research (BMBF) (Germany) ; Associazione Italiana per la Ricerca sul CancroAIRCItaly, Compagnia di SanPaolo and National Research Council (Italy) ; Dutch Ministry of Public Health, Welfare and Sports (VWS) , Netherlands Can-cer Registry (NKR) , LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland) , World Cancer Research Fund (WCRF) , Statistics Netherlands (The Netherlands) ; Health Research Fund (FIS) -Instituto de Salud Carlos III (ISCIII) , Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology-ICO (Spain) ; Swedish Cancer Society, Swedish Research Council and County Councils of Skkne and Vasterbotten (Sweden) ; Cancer Research UK (14136 to EPICNorfolk; C8221/A29017 to EPICOxford) , Medical Research Council (1000143 to EPICNorfolk; MR/M012190/1 to EPICOxford) . (United Kingdom) ., Background. Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from853 case-control pairs fromthe European Prospective Investigation into Cancer and Nutrition (EPIC). Methods. A total of 129metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed. Results. After adjustment for body mass index, sphingomyelin [SM] C18:0was positively (OR1SD: 1.18,95%CI: 1.05–1.33), and glycine, serine, and free carnitine (C0) were inversely (OR1SD: 0.89, 95% CI: 0.80–0.99; OR1SD: 0.89, 95% CI: 0.79–1.00 and OR1SD: 0.91, 95% CI: 0.81–1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR1SD: 1.14, 95% CI: 1.02–1.28) and that of short chain to free acylcarnitines (OR1SD: 1.12, 95% CI: 1.00–1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results. Conclusion. These findings suggest that variation in levels of glycine, serine, SMC18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention., Cancer Research UK C19335/A21351, Imperial College Experimental Cancer Medicine Centre Imperial College Cancer Research UK Centre, NIHR Imperial Biomedical Research Centre, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France) Institut Gustave Roussy (France) Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, German Cancer Research Center (DKFZ) (Germany) German Institute of Human Nutrition PotsdamRehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro Compagnia di San Paolo Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII) (Spain), Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Catalan Institute of Oncology-ICO (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skkne (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/M012190/1
Published: 2021

42. Infection with genotoxin-producing Salmonella enterica synergises with loss of the tumour suppressor APC in promoting genomic instability via the PI3K pathway in colonic epithelial cells

Author: Puran Chen, Océane C.B. Martin, Mattias Svensson, Teresa Frisan, Jerry W. Shay, Maria G. Masucci, Anna Bergonzini, J. Dupuy, Federica D’Amico, Department of Cell and Molecular Biology, Karolinska Institutet [Stockholm], Department of Molecular Biology, Umeå University, Department of Medicine, The University of Sydney, University of Texas Southwestern Medical Center, Prévention et promotion de la cancérogénèse par les aliments (ToxAlim-PPCA), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Cancerfonden, Umea University, Cancer Research Foundation in Northern Sweden, Kempestiftelserna, Lillian Sagens och Curt Ericssons forskningsstiftelse, Swedish Research Council, Swedish Cancer Society, Martin O.C.B., Bergonzini A., D'Amico F., Chen P., Shay J.W., Dupuy J., Svensson M., Masucci M.G., and Frisan T.
Subjects: Genome instability, Colorectal cancer, Carcinogenesis, tumour-suppressor gene, Toxicology, DNA damage response, law.invention, Mice, Phosphatidylinositol 3-Kinases, bacterial genotoxin, law, Tumor Microenvironment, Genes, Tumor Suppressor, Research Articles, tumour‐suppressor gene, 0303 health sciences, biology, Microbiology and Parasitology, Salmonella enterica, Microbiologie et Parasitologie, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Adenomatous Polyposis Coli, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Salmonella Infections, organotypic del, Colorectal Neoplasms, Signal Transduction, Research Article, DNA repair, Colon, Immunology, Microbiology, Genomic Instability, Cell Line, 03 medical and health sciences, Virology, medicine, Animals, Humans, APC, bacteria and cancer, organotypic model, PI3K/AKT/mTOR pathway, Carcinogen, Toxicologie, 030304 developmental biology, 030306 microbiology, Epithelial Cells, Cell Cycle Checkpoints, biology.organism_classification, medicine.disease, Mikrobiologi, Cancer research, Suppressor, Bacteria, DNA Damage, Mutagens
Abstract: International audience; Several commensal and pathogenic Gram-negative bacteria produce DNA-damaging toxins that are considered bona fide carcinogenic agents. The microbiota of colorectal cancer (CRC) patients is enriched in genotoxin-producing bacteria, but their role in the pathogenesis of CRC is poorly understood. The adenomatous polyposis coli (APC) gene is mutated in familial adenomatous polyposis and in the majority of sporadic CRCs. We investigated whether the loss of APC alters the response of colonic epithelial cells to infection by Salmonella enterica, the only genotoxin-producing bacterium associated with cancer in humans. Using 2D and organotypic 3D cultures, we found that APC deficiency was associated with sustained activation of the DNA damage response, reduced capacity to repair different types of damage, including DNA breaks and oxidative damage, and failure to induce cell cycle arrest. The reduced DNA repair capacity and inability to activate adequate checkpoint responses was associated with increased genomic instability in APC-deficient cells exposed to the genotoxic bacterium. Inhibition of the checkpoint response was dependent on activation of the phosphatidylinositol 3-kinase pathway. These findings highlight the synergistic effect of the loss of APC and infection with genotoxin-producing bacteria in promoting a microenvironment conducive to malignant transformation.
Published: 2019

43. Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures

Author: Konstantinos Karakostis, Robin Fåhraeus, Bodescot, Myriam, Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical Biosciences [Umeå, Suède], Umeå University, Regional centre for applied molecular oncology [Brno, République tchèque] (RECAMO), Masaryk Memorial Cancer Institute (MMCI), Cancerforskningsfonden Norr [AMP 16-823], Cancerfonden (180296), Vetenskapsradet and MEYS-NPS [I-L01413]., and Masaryk Memorial Cancer Institute [Brno, République tchèque] (MMCI)
Subjects: 0301 basic medicine, Cancer Research, mRNA translation, Review, 0302 clinical medicine, Protein-RNA interactions, Neoplasms, biology, Chemistry, Biochemistry and Molecular Biology, RNA-Binding Proteins, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Non-coding RNA, Cell biology, Ubiquitin ligase, Ciona intestinalis, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, Mdm2, Molecular basis of disease, Protein Binding, RNA world, [SDV.CAN]Life Sciences [q-bio]/Cancer, Intrinsically disordered proteins, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Genetic Predisposition to Disease, Protein Interaction Domains and Motifs, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Nucleic acid structure, Transcription factor, Messenger RNA, Cancer och onkologi, Gene Expression Profiling, Tumor Suppressor Proteins, RNA, 030104 developmental biology, Cancer and Oncology, biology.protein, Tumor Suppressor Protein p53, Transcriptome, Biokemi och molekylärbiologi
Abstract: Structured RNA regulatory motifs exist from the prebiotic stages of the RNA world to the more complex eukaryotic systems. In cases where a functional RNA structure is within the coding sequence a selective pressure drives a parallel co-evolution of the RNA structure and the encoded peptide domain. The p53-MDM2 axis, describing the interactions between the p53 tumor suppressor and the MDM2 E3 ubiquitin ligase, serves as particularly useful model revealing how secondary RNA structures have co-evolved along with corresponding interacting protein motifs, thus having an impact on protein – RNA and protein – protein interactions; and how such structures developed signal-dependent regulation in mammalian systems. The p53(BOX-I) RNA sequence binds the C-terminus of MDM2 and controls p53 synthesis while the encoded peptide domain binds MDM2 and controls p53 degradation. The BOX-I peptide domain is also located within p53 transcription activation domain. The folding of thep53mRNA structure has evolved from temperature-regulated in pre-vertebrates to an ATM kinase signal-dependent pathway in mammalian cells. The protein – protein interaction evolved in vertebrates and became regulated by the same signaling pathway. At the same time the protein - RNA and protein - protein interactions evolved, the p53 trans-activation domain progressed to become integrated into a range of cellular pathways. We discuss how a single synonymous mutation in the BOX-1, the p53(L22 L), observed in a chronic lymphocyte leukaemia patient, prevents the activation of p53 following DNA damage. The concepts analysed and discussed in this review may serve as a conceptual mechanistic paradigm of the co-evolution and function of molecules having roles in cellular regulation, or the aetiology of genetic diseases and how synonymous mutations can affect the encoded protein.
Published: 2019

44. In Cellulo Protein-mRNA Interaction Assay to Determine the Action of G-Quadruplex-Binding Molecules

Author: Martins, Rodrigo Prado, Findakly, Sarah, Daskalogianni, Chrysoula, Teulade-Fichou, Marie-Paule, Blondel, Marc, Fåhraeus, Robin, Université Paris Diderot - Paris 7 (UPD7), University of Gdańsk (UG), Université Paris-Sud - Paris 11 (UP11), Université de Bretagne Occidentale, and La Ligue contre le cancer, La Ligue contre le cancer CSIRGO, Fondation ARC, Institut National du cancer (INCa), Cancerfonden (16059), Cancerforskningsfondedn Norr and Vetenskapsrade, project MEYS-NPS (I-L01413).
Subjects: [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], EBNA1, Communication, structure-activity relationship, Biochemistry and Molecular Biology, RNA-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Phosphoproteins, G-quadruplexes, pyridostatin, Epstein-Barr virus (EBV), lcsh:QD241-441, Epstein-Barr Virus Nuclear Antigens, lcsh:Organic chemistry, PhenDC3, Cell Line, Tumor, Aminoquinolines, Humans, Biological Assay, RNA, Messenger, Picolinic Acids, protein-mRNA interactions, Biokemi och molekylärbiologi
Abstract: Supplementary Materials; International audience; Protein-RNA interactions (PRIs) control pivotal steps in RNA biogenesis, regulate multiple physiological and pathological cellular networks, and are emerging as important drug targets. However, targeting of specific protein-RNA interactions for therapeutic developments is still poorly advanced. Studies and manipulation of these interactions are technically challenging and in vitro drug screening assays are often hampered due to the complexity of RNA structures. The binding of nucleolin (NCL) to a G-quadruplex (G4) structure in the messenger RNA (mRNA) of the Epstein-Barr virus (EBV)-encoded EBNA1 has emerged as an interesting therapeutic target to interfere with immune evasion of EBV-associated cancers. Using the NCL-EBNA1 mRNA interaction as a model, we describe a quantitative proximity ligation assay (PLA)-based in cellulo approach to determine the structure activity relationship of small chemical G4 ligands. Our results show how different G4 ligands have different effects on NCL binding to G4 of the EBNA1 mRNA and highlight the importance of in-cellulo screening assays for targeting RNA structure-dependent interactions.
Published: 2018

45. Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence

Author: Verena Königer, D. Scott Merrell, Roman Andriiovych Moskalenko, Rainer Haas, Thomas Borén, Sara Henriksson, Jafar Mahdavi, Abhijit Chowdhury, Johan Ögren, Anders Hofer, Jay V. Solnick, Dan Danielsson, Sara K. Lindén, Dag Ilver, Konstantinos S. Papadakos, Susanne Vikström, Jörgen Ådén, Jan Holgersson, Gerhard Gröbner, Alexej Schmidt, Jeanna Bugaytsova, Oscar Björnham, Göran O. Bylund, Rolf Sjöström, Stefan Oscarson, Dionyssios N. Sgouras, Lori M. Hansen, Yevgen A Chernov, Anders Esberg, Kristof Moonens, Christopher Aisenbrey, Charles Kelly, Ludmilla A. Morozova-Roche, Jeannette M. Whitmire, Beatriz Martinez-Gonzalez, Asish K. Mukhopadhyay, Angela Eldridge, Nicklas Strömberg, Robert H. Gilman, Andre Dubois, Lars Engstrand, Staffan Schedin, Brett A. Chromy, Justine Younson, Matthew Goldman, Anna Shevtsova, Macarena P. Quintana-Hayashi, Hui Liu, Magnus Unemo, Lena Rakhimova, Anna Åberg, Sebastian Suerbaum, Anna Arnqvist, Pär Gideonsson, Maréne Landström, Douglas E. Berg, Kristoffer Brännström, Anders Olofsson, Melissa Mendez, G. Balakrish Nair, Han Remaut, Umeå University, School of Life Sciences, University of Nottingham, UK (UON), Sahlgrenska Academy at University of Gothenburg [Göteborg], Université libre de Bruxelles (ULB), VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Sumy State University, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), Uniformed Services University of the Health Sciences (USUHS), King‘s College London, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), School of Digestive and Liver Diseases [Kolkata] (SDLD), National Institute of Cholera and Enteric Diseases, Translational Health Science and Technology Institute [Faridabad] (THSTI), Institut Pasteur Hellénique, Réseau International des Instituts Pasteur (RIIP), Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska Institutet [Stockholm], Örebro University Hospital [Örebro, Sweden], Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), School of Chemistry and Chemical Biology (UCD), University College Dublin [Dublin] (UCD), University of California [Davis] (UC Davis), University of California, German Center for Infection Research, Partnersite Munich (DZIF), Département d'Informatique [Bruxelles] (ULB), Faculté des Sciences [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), University of California [San Diego] (UC San Diego), This work was supported by grants from Vetenskapsrådet (VR/M) to T.B. and S.K.L., Cancerfonden to T.B. and A.A., VR/NT to A.A. and S. Schedin, Formas to S.K.L., the J.C. Kempe and Seth M. Kempe Memorial Foundation, the Knut and Alice Wallenberg Foundation (2012.0090) to T.B. and M.L., European Union Seventh Framework Program GastricGlycoExplorer ITN grant number 316929 to T.B. and Y.A.C., Magn. Bergvall’s Foundation to S. Schedin, DFG (SFB 900/A1) to S. Suerbaum, DFG (HA2697/16-1) to R.H., FP6 ANR-06-PATHO-00701 ERA-NET and Actions Concertées Inter-Pasteuriennes (ACIP) (2006) to D.N.S., NIH R01DK063041 to D.E.B., NIH CA082312 to D.S.M., NIH AI070803 and AI081037 to J.V.S., CSIR project, India (No. 37(1640)/14/EMR –II) to A.K.M., and VIB and FWO (grants: G033717N and 12H8416N) to K.M. and H.R., This paper is dedicated to the memory of our friend, collaborator, and co-author Dr. Andre Dubois, a great scientist who contributed importantly both intellectually and materially to this project. We thank S. Michopoulos and G. Mantzaris for H. pylori clinical isolates and Ö. Furberg (NoPolo.se), N. Ulander (softplanbangkok.com), S. Lindström, and M. Borén for the digital movie, tech, art, and figure work, respectively., Vrije Universiteit Brussel, Basic (bio-) Medical Sciences, Structural Biology Brussels, and Department of Bio-engineering Sciences
Subjects: 0301 basic medicine, MESH: Hydrogen-Ion Concentration, Gastric acidity, MESH: Helicobacter Infections/pathology, MESH: Helicobacter pylori/physiology, Disease, adaptation, Bacterial Adhesion, polymorphism, acid responsiveness, MESH: Bacterial Adhesion, Bacterial, Hydrogen-Ion Concentration, gastric acidity, Adhesins, 3. Good health, Cell and molecular biology, medicine.anatomical_structure, Infectious Diseases, MESH: Gastric Mucosa/microbiology, Medical Microbiology, 030106 microbiology, Immunology, Digestive Diseases - (Peptic Ulcer), Biology, blood group antigen-binding adhesion, Microbiology, Helicobacter Infections, diversity, Vaccine Related, 03 medical and health sciences, Virology, ABO blood group system, Biodefense, Gastric mucosa, medicine, MESH: Helicobacter Infections/microbiology, multimerization, Adhesins, Bacterial, subpopulations, Helicobacter pylori, Prevention, gastric cancer, MESH: Adhesins, Bacterial/metabolism, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Gastric Mucosa/pathology, Bacterial adhesin, Chronic infection, 030104 developmental biology, Emerging Infectious Diseases, Gastric Mucosa, Parasitology, Digestive Diseases
Abstract: The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen andthat bio-selection and changes in BabA bindingproperties through mutation and recombination with babA-related genes are selected by differencesamong individuals and by changes in gastric acidity over time. These processes generate diverse H.pylori subpopulations, in which BabA's adaptive evolution contributes to H.pylori persistence and overt gastric disease.
Published: 2017

46. Glioblastoma and glioblastoma stem cells are dependent on functional MTH1

Author: Alberto J. Schuhmacher, Thomas Helleday, Steven J. Edwards, Pegah Rouhi, Kumar Sanjiv, Helge Gad, Linda Pudelko, Christina Kalderén, Ulrika Warpman Berglund, Massimo Squatrito, Andreas Höglund, Lars Bräutigam, Daniel Hägerstrand, Fundación Seve Ballesteros, Marie Curie, Knut and Alice Wallenberg Foundation, Swedish Foundation for Strategic Research, Swedish Cancer Society (Cancerfonden), Swedish Research Council, Göran Gustafsson Foundation, Swedish Children’s Cancer Foundation, Swedish Pain Relief Foundation, and Torsten and Ragnar Söderberg Foundation
Subjects: 0301 basic medicine, cancer stem cells, Nudt1, DNA damage, 03 medical and health sciences, glioblastoma multiforme, Downregulation and upregulation, Cancer stem cell, In vivo, Medicine, business.industry, urogenital system, Cancer, medicine.disease, In vitro, 3. Good health, nervous system diseases, MTH1, 030104 developmental biology, Oncology, Immunology, Cancer cell, Cancer research, Stem cell, business, Priority Research Paper
Abstract: Glioblastoma multiforme (GBM) is an aggressive form of brain cancer with poor prognosis. Cancer cells are characterized by a specific redox environment that adjusts metabolism to its specific needs and allows the tumor to grow and metastasize. As a consequence, cancer cells and especially GBM cells suffer from elevated oxidative pressure which requires antioxidant-defense and other sanitation enzymes to be upregulated. MTH1, which degrades oxidized nucleotides, is one of these defense enzymes and represents a promising cancer target. We found MTH1 expression levels elevated and correlated with GBM aggressiveness and discovered that siRNA knock-down or inhibition of MTH1 with small molecules efficiently reduced viability of patient-derived GBM cultures. The effect of MTH1 loss on GBM viability was likely mediated through incorporation of oxidized nucleotides and subsequent DNA damage. We revealed that MTH1 inhibition targets GBM independent of aggressiveness as well as potently kills putative GBM stem cells in vitro. We used an orthotopic zebrafish model to confirm our results in vivo and light-sheet microscopy to follow the effect of MTH1 inhibition in GBM in real time. In conclusion, MTH1 represents a promising target for GBM therapy and MTH1 inhibitors may also be effective in patients that suffer from recurring disease. We thank the staff of the zebrafish core facility for their excellent service, K.Edfelt and C.Sjögren for administrative help, S.Eriksson and F.Pineiro for lab support, and J.Carreras-Puigvert for help with the cell profiler software. We acknowledge M.Scobie, K.Vallin, T.Koolmeister, M.Henriksson, O.Wallner and S.Jacques for synthesis of MTH1 inhibitors and M.Guo and M.Nister for providing the GBM cultures (all Karolinska Institutet). Sí
Published: 2017

47. Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

Author: Rongrong Fan, Toby Lawrence, Judith Aron-Wisnewsky, Fabienne Foufelle, Zhiqiang Huang, Patricia Ancel, Anastasios E. Damdimopoulos, Antoine Soprani, Isabelle Hainault, Ning Liang, Saioa Goñi, Raphaelle Ballaire, Jean-François Gautier, Amine Toubal, Karima Drareni, Fawaz Alzaid, Eckardt Treuter, Nicolas Venteclef, 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), Swedish Research Council (Vetenskapsradet), Swedish Cancer Society (Cancerfonden), Swedish Diabetes Foundation (Diabetesfonden), Novo Nordisk Foundation (Novo Nordisk Fonden), Center for Biosciences (CIMED) at Karolinska Institutet, French National Agency of Research (CONRAD), French National Agency of Research [ANR CE12 2014], French National Agency of Research (FATMAC), Region Ile de France (CORDDIM), Paris city (EMERGENCE), French Foundation for Medical Research [Equipe FRM DEQ20140329504], French government [ANR-10-IAH, ICAN MetaMACS], Assistance Publique des Hopitaux de Paris (APHP), Programs of Clinical Investigation (CRC Fibrota) [AOO759-32], PHRC Glucostress [P081122], 'Ministere de la Recherche et de l'Enseignement superieur', China Scholarship Council (CRC), Karolinska Institutet (KID), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
Subjects: 0301 basic medicine, Male, adipose-tissue macrophages, Adipose tissue, Gene Expression, Mice, Obese, Type 2 diabetes, Mice, RNA, Small Interfering, ppar-gamma, Epigenomics, Bone Marrow Transplantation, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Intracellular Signaling Peptides and Proteins, General Medicine, Middle Aged, Flow Cytometry, Immunohistochemistry, GPS2, Adipose Tissue, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Adult, medicine.medical_specialty, Blotting, Western, kappa-b, Inflammation, Biology, Diet, High-Fat, Real-Time Polymerase Chain Reaction, General Biochemistry, Genetics and Molecular Biology, insulin-resistance, 03 medical and health sciences, Insulin resistance, Stress, Physiological, Diabetes mellitus, Internal medicine, medicine, Animals, Humans, Obesity, gene, nuclear receptor corepressor, alternative activation, polarization, Macrophages, medicine.disease, signaling pathways, Transplantation, 030104 developmental biology, Endocrinology, RAW 264.7 Cells, Diabetes Mellitus, Type 2, inflammation, Insulin Resistance
Abstract: International audience; Humans with obesity differ in their susceptibility to developing insulin resistance and type 2 diabetes (T2D). This variation may relate to the extent of adipose tissue (AT) inflammation that develops as their obesity progresses. The state of macrophage activation has a central role in determining the degree of AT inflammation and thus its dysfunction, and these states are driven by epigenomic alterations linked to gene expression. The underlying mechanisms that regulate these alterations, however, are poorly defined. Here we demonstrate that a co-repressor complex containing G protein pathway suppressor 2 (GPS2) crucially controls the macrophage epigenome during activation by metabolic stress. The study of AT from humans with and without obesity revealed correlations between reduced GPS2 expression in macrophages, elevated systemic and AT inflammation, and diabetic status. The causality of this relationship was confirmed by using macrophage-specific Gps2-knockout (KO) mice, in which inappropriate co-repressor complex function caused enhancer activation, pro-inflammatory gene expression and hypersensitivity toward metabolic-stress signals. By contrast, transplantation of GPS2-overexpressing bone marrow into two mouse models of obesity (ob/ob and diet-induced obesity) reduced inflammation and improved insulin sensitivity. Thus, our data reveal a potentially reversible disease mechanism that links co-repressor-dependent epigenomic alterations in macrophages to AT inflammation and the development of T2D.
Published: 2016

48. Insights into Hox protein function from a large scale combinatorial analysis of protein domains

Author: K. VijayRaghavan, Samir Merabet, Mehdi Saadaoui, Bruno Monier, Jacques Pradel, Stefan Thor, Laurent Perrin, Daniel Karlsson, Yacine Graba, Richa Dixit, Isma Litim-Mecheri, Christine Brun, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical and Experimental Medicine, Linköping University (LIU), National Centre for Biological Sciences [TIFR] (NCBS), Tata Institute for Fundamental Research (TIFR), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Work in the YG and JP laboratory is supported by the CNRS, Université de la Méditerranée, and grants from ANR, FRM, CEFIPRA, and ARC, work in the ST laboratory is supported by the Swedish Research Council, the Swedish Strategic Research Foundation, the Knut and Alice Wallenberg Foundation, the Swedish 'Hjärnfonden,' 'Cancerfonden,' and the Swedish Royal Academy of Sciences, work in the LP laboratory is supported by the CNRS, Université de la Méditerrannée, and grants from ANR and AFM., and Autard, Delphine
Subjects: Central Nervous System, Cancer Research, Gene Expression, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Protein sequencing, MESH: Gene Expression Regulation, Developmental, Morphogenesis, Drosophila Proteins, Protein function prediction, MESH: Animals, Pattern Formation, Nuclear protein, Genetics (clinical), MESH: Genetic Association Studies, Genetics, 0303 health sciences, Drosophila Melanogaster, Gene Expression Regulation, Developmental, Nuclear Proteins, Animal Models, MESH: Transcription Factors, MESH: Wnt1 Protein, DNA-Binding Proteins, Drosophila Protein, Research Article, MESH: Body Patterning, MESH: Mutation, lcsh:QH426-470, MESH: Drosophila Proteins, Protein domain, Wnt1 Protein, Computational biology, Biology, DNA-binding protein, MESH: Drosophila melanogaster, 03 medical and health sciences, Model Organisms, Animals, MESH: Central Nervous System, Cell Lineage, Molecular Biology, Transcription factor, Genetic Association Studies, Ecology, Evolution, Behavior and Systematics, Body Patterning, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Evolutionary Developmental Biology, Robustness (evolution), Molecular Development, MESH: Cell Lineage, Protein Structure, Tertiary, lcsh:Genetics, Mutation, Gene Function, Organism Development, MESH: Nuclear Proteins, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors, Developmental Biology
Abstract: Protein function is encoded within protein sequence and protein domains. However, how protein domains cooperate within a protein to modulate overall activity and how this impacts functional diversification at the molecular and organism levels remains largely unaddressed. Focusing on three domains of the central class Drosophila Hox transcription factor AbdominalA (AbdA), we used combinatorial domain mutations and most known AbdA developmental functions as biological readouts to investigate how protein domains collectively shape protein activity. The results uncover redundancy, interactivity, and multifunctionality of protein domains as salient features underlying overall AbdA protein activity, providing means to apprehend functional diversity and accounting for the robustness of Hox-controlled developmental programs. Importantly, the results highlight context-dependency in protein domain usage and interaction, allowing major modifications in domains to be tolerated without general functional loss. The non-pleoitropic effect of domain mutation suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversification during evolution, so far thought to rely largely on modification in gene cis-regulatory sequences., Author Summary Proteins perform essential regulatory functions, including control of gene transcription, a process central to development, evolution, and disease. While protein domains important for protein activity have been identified, how they act together to define the activity of a protein remains poorly explored. The predominant view influenced by prokaryotic transcription factors is that protein domains constitute independent functional modules, required for all aspects of protein activity. In this study, we used Hox proteins, evolutionarily conserved transcription factors playing key roles in the establishment of animal body plans, to examine how protein domains collectively shape protein activity. Results obtained using a broad range of biological readouts highlight a context-dependency in protein domain usage and interaction, revealing that protein domains are non-pleoitropic in nature. This suggests that protein modification may contribute more broadly to molecular changes underlying morphological diversity, so far thought to rely largely on modification of gene cis-regulatory sequences.
Published: 2011

49. Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses

Author: Elisabeth Sundström, Saima Imran, Monika Seltenhammer, Giorgia Egidy, Leif Andersson, Cécile Campagne, Gerli Pielberg, Pedro Sousa, Anna Golovko, Lin Jiang, Mats J. Olsson, Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Chinese Academy of Agricultural Sciences (CAAS), Génétique Moléculaire et Cellulaire (UGMC), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), École nationale vétérinaire d'Alfort (ENVA), Department of Medical Biochemistry and Microbiology, Medizinische Universität Wien = Medical University of Vienna, Uppsala University Hospital, Uppsala Science Park, Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS), Department of Animal Bredding and Genetics, Swedish University of Agricultural Sciences (SLU), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), École nationale vétérinaire - Alfort (ENVA), Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The University of Sydney, This work was supported by Foundation for Equine Research (Stiftelsen Hästforskning, grant to AG), Swedish Cancer Society (Cancerfonden, and grant to LA) and Mitjaville and Ministère de la Recherche et Technologie fellowships (grant to CC).
Subjects: MAPK/ERK pathway, Grey horse, Cancer Research, Melanoma, ERK pathway, STX17, melanocytes, [SDV]Life Sciences [q-bio], Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), MESH: Genotype, MESH: Animals, MESH: Genetic Variation, Mitogen-Activated Protein Kinase 1, Oncogene Proteins, Tumor, Mitogen-Activated Protein Kinase 3, Melanocytes, Animals, Cell Line, Tumor, Genetic Variation, Genotype, Horse Diseases, Horses, Humans, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), MAP Kinase Signaling System, Kinase, Oncology, MESH: Mitogen-Activated Protein Kinase 3, GNAQ, MESH: Mitogen-Activated Protein Kinase 1, Research Article, MESH: Cell Line, Tumor, MESH: Melanoma, Biology, Syntaxin 17, Cell Line, MESH: Proto-Oncogene Proteins p21(ras), MESH: Oncogene Proteins, MESH: Melanocytes, medicine, Genetics, MESH: Horses, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), PI3K/AKT/mTOR pathway, MESH: Proto-Oncogene Proteins B-raf, MESH: Humans, GNA11, MESH: MAP Kinase Signaling System, medicine.disease, Cutaneous melanoma, Cancer research, MESH: Horse Diseases
Abstract: Background Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses. Methods Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting. Results We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. Conclusions These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this pathway during melanomagenesis. These findings are consistent with the universal importance of the ERK pathway in melanomagenesis and may have valuable implications for human melanoma research.
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50. Co-creation of a digital platform for peer support in a community of adolescent and young adult patients during and after cancer.

Author: Olsson M, Eliasson I, Kautsky S, Hård Af Segerstad Y, and Nilsson S
Subjects: Humans, Adolescent, Female, Male, Sweden, Young Adult, Adult, Adaptation, Psychological, Cancer Survivors psychology, Loneliness psychology, Peer Group, Neoplasms psychology, Social Support
Abstract: Purpose: Adolescents and young adults (AYAs) diagnosed with cancer report psychological challenges and social isolation. Peer support has been shown to be a valuable resource for coping with these experiences. The aim of this study was through co-creation map the needs for peer support among AYA cancer patients in Sweden; and building on these results to develop and test a prototype of a digital tool for peer support., Method: The study was conducted in co-creation in a team consisting of AYA cancer patients, researchers, and a health tech company in Sweden. Through interviews the needs for emotional support were investigated. Based on this information, a prototype of a digital platform for peer support was co-created by the team. The platform was tested and evaluated through an online survey and follow-up interviews as part of the development process., Results: AYAs expressed feelings of loneliness and a desire to process their cancer experiences with peers. A prerequisite for a digital platform for peer support was the assurance of a high degree of security. Piloting the prototype, 87% reported feeling secure, all participants found it valuable to interact with peers on the platform. In the follow-up interviews, AYAs emphasizing the need to simplify this process while maintaining stringent security measures., Conclusion: Co-creating tools for support together with AYAs ensures relevance and usability. A secure digital platform for peer support represents a complement to other existing forms of support. The presence of moderators was found to enhance security. Further development of the platform's log-in procedure is necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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