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1. Wharton’s Jelly Mesenchymal Stromal Cells and Derived Extracellular Vesicles as Post-Myocardial Infarction Therapeutic Toolkit: An Experienced View

Author

Muñoz-Domínguez, Noelia, Roura, Santiago, Prat-Vidal, Cristina, Vives Armengol, Joaquim, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Muñoz-Domínguez N] Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Barcelona, Spain. [Roura S] ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Can Ruti Campus, Badalona, Spain. Heart Institute (iCor), Germans Trias i Pujol University Hospital, Badalona, Spain. CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain. Faculty of Medicine, University of Vic-Central University of Catalonia, Vic, Spain. [Prat-Vidal C] ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Can Ruti Campus, Badalona, Spain. Heart Institute (iCor), Germans Trias i Pujol University Hospital, Badalona, Spain. CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain. Institut d’Investigació Biomèdica de Bellvitge—IDIBELL, L’Hospitalet de Llobregat, Spain. [Vives J] Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Barcelona, Spain. Grup d'Enginyeria de Teixits Musculoesquelètics, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
biomanufacturing, Cell, Mesenchymal stromal cells, Pharmaceutical Science, Context (language use), Review, Cardiac tissue engineering, Extracellular vesicles, clinical translation, Cardiovascular Diseases::Heart Diseases::Myocardial Ischemia::Myocardial Infarction [DISEASES], cardiac tissue engineering, Pharmacy and materia medica, Tissue engineering, Wharton's jelly, medicine, Extracellular, Cells::Cellular Structures::Extracellular Space::Extracellular Vesicles [ANATOMY], Myocardial infarction, Infart de miocardi - Tractament, células::células del tejido conectivo::células del estroma::células madre mesenquimatosas [ANATOMÍA], Cells::Connective Tissue Cells::Stromal Cells::Mesenchymal Stem Cells [ANATOMY], Biomanufacturing, Wharton’s jelly, business.industry, Clinical translation, Teràpia cel·lular, Mesenchymal stem cell, células::estructuras celulares::espacio extracelular::vesículas extracelulares [ANATOMÍA], medicine.disease, enfermedades cardiovasculares::enfermedades cardíacas::isquemia miocárdica::infarto de miocardio [ENFERMEDADES], RS1-441, medicine.anatomical_structure, myocardial infarction, Cancer research, business, extracellular vesicles, mesenchymal stromal cells
Abstract

Gelatina de Wharton; Enginyeria de teixits cardíacs; Infart de miocardi Gelatina de Wharton; Ingeniería de tejidos cardíacos; Infarto de miocardio Wharton’s jelly; Cardiac tissue engineering; Myocardial infarction Outstanding progress has been achieved in developing therapeutic options for reasonably alleviating symptoms and prolonging the lifespan of patients suffering from myocardial infarction (MI). Current treatments, however, only partially address the functional recovery of post-infarcted myocardium, which is in fact the major goal for effective primary care. In this context, we largely investigated novel cell and TE tissue engineering therapeutic approaches for cardiac repair, particularly using multipotent mesenchymal stromal cells (MSC) and natural extracellular matrices, from pre-clinical studies to clinical application. A further step in this field is offered by MSC-derived extracellular vesicles (EV), which are naturally released nanosized lipid bilayer-delimited particles with a key role in cell-to-cell communication. Herein, in this review, we further describe and discuss the rationale, outcomes and challenges of our evidence-based therapy approaches using Wharton’s jelly MSC and derived EV in post-MI management. This work has been developed in the context of ADVANCE(CAT) with the support of ACCIÓ (Catalonia Trade & Investment; Generalitat de Catalunya) and the European Community under the Catalonian ERDF operational program (European Regional Development Fund) 2014–2020, Generalitat de Catalunya (Departament de Salut) PERIS Acció Instrumental de Programes de Recerca Orientats (SLT002/16/00234), Spanish Society of Cardiology, Catalan Society of Cardiology, Fundació bancària La Caixa, CIBER Cardiovascular (CB16/11/00403) and by the Spanish Cell Therapy Network (TerCel, expedient numbers: RD16/0011/0006 & RD16/0011/0028). Projects PI19/01788, PI17/01487, PIC18/00014, ICI19/00039, PI18/00256, PI18/01227, ICI20/00135 are funded by Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF)—A way to build Europe. Projects SAF2017-84324-C2-1-R and PID2019-110137RB-I00 are funded the Spanish Ministry of Economy and Competitiveness-MICINN. Our laboratories are awarded by the Generalitat de Catalunya’s AGAUR as Consolidated Research Groups (references 2017-SGR-483, 2017-SGR-719 and 2019PROD00122), and by the Catalan Heath Institute.

Published
2021

2. Osteogenic commitment of Wharton's jelly mesenchymal stromal cells: mechanisms and implications for bioprocess development and clinical application

Author

Ana Gámez-Valero, Santiago Roura, Raquel Rojas-Márquez, Francesc E. Borràs, Raquel Cabrera-Pérez, Marta Monguió-Tortajada, Joaquim Vives, Institut Català de la Salut, [Cabrera-Pérez R] Cell Therapy Service, Blood and Tissue Bank (BST), Barcelona, Catalonia, Spain. Grup Enginyeria Tissular Musculoesquelètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Monguió-Tortajada M, Gámez-Valero A] REMAR-IVECAT Group, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Catalonia, Spain. [Rojas-Márquez R] Cell Therapy Service, Blood and Tissue Bank (BST), Barcelona, Catalonia, Spain. Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), Barcelona, Catalonia, Spain. [Borràs FE] REMAR-IVECAT Group, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Catalonia, Spain. Nephrology Service, Germans Trias i Pujol University Hospital, Badalona, Catalonia, Spain. [Roura S] ICREC Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Catalonia, Spain. [Vives J] Cell Therapy Service, Blood and Tissue Bank (BST), Barcelona, Catalonia, Spain. Grup Enginyeria Tissular Musculoesquelètica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Proteomics, Cell, fenómenos fisiológicos nerviosos y musculoesqueléticos::fenómenos fisiológicos musculoesqueléticos::desarrollo musculoesquelético::biomineralización::desarrollo óseo::osteogénesis [FENÓMENOS Y PROCESOS], Mesenchymal stromal cells, Bone Morphogenetic Protein 2, Medicine (miscellaneous), Bone Marrow Cells, Biology, Real-Time Polymerase Chain Reaction, Biochemistry, Genetics and Molecular Biology (miscellaneous), Bone morphogenetic protein 2, Regenerative medicine, Ossos - Creixement, lcsh:Biochemistry, Osteogenesis, Osteogenic differentiation, Wharton's jelly, medicine, Humans, lcsh:QD415-436, Bone marrow, Bone regeneration, lcsh:R5-920, Wharton’s jelly, Cèl·lules de la medul·la òssia, Research, Mesenchymal stem cell, Cell Differentiation, Mesenchymal Stem Cells, Cell Biology, células::células de la médula ósea [ANATOMÍA], medicine.anatomical_structure, Culture Media, Conditioned, Cancer research, Molecular Medicine, Stem cell, Cells::Bone Marrow Cells [ANATOMY], lcsh:Medicine (General), Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Development::Biomineralization::Bone Development::Osteogenesis [PHENOMENA AND PROCESSES]
Abstract

Cèl·lules estromals mesenquimals; Gelatina de Wharton; Diferenciació osteogènica Células estromales mesenquimales; Gelatina de Wharton; Diferenciación osteogénica Mesenchymal stromal cells, Wharton’s jelly; Osteogenic differentiation Background Orthopaedic diseases are one of the major targets for regenerative medicine. In this context, Wharton’s jelly (WJ) is an alternative source to bone marrow (BM) for allogeneic transplantation since its isolation does not require an invasive procedure for cell collection and does not raise major ethical concerns. However, the osteogenic capacity of human WJ-derived multipotent mesenchymal stromal cells (MSC) remains unclear. Methods Here, we compared the baseline osteogenic potential of MSC from WJ and BM cell sources by cytological staining, quantitative real-time PCR and proteomic analysis, and assessed chemical and biological strategies for priming undifferentiated WJ-MSC. Concretely, different inhibitors/activators of the TGFβ1-BMP2 signalling pathway as well as the secretome of differentiating BM-MSC were tested. Results Cytochemical staining as well as gene expression and proteomic analysis revealed that osteogenic commitment was poor in WJ-MSC. However, stimulation of the BMP2 pathway with BMP2 plus tanshinone IIA and the addition of extracellular vesicles or protein-enriched preparations from differentiating BM-MSC enhanced WJ-MSC osteogenesis. Furthermore, greater outcome was obtained with the use of conditioned media from differentiating BM-MSC. Conclusions Altogether, our results point to the use of master banks of WJ-MSC as a valuable alternative to BM-MSC for orthopaedic conditions. Work in our laboratory is supported by the Spanish Cell Therapy Network (TerCel, expedient No. RD16/0011/0028 and RD16/00111/0006), Ministerio de Ciencia Innovación y Universidades de España (Instituto de Salud Carlos III, expedient No. PI19/01788), Fundació la Marató de TV3 (expedient number: 122831), and ISCIII-REDinREN (RD16/0009 Feder Funds), and developed in the context of AdvanceCat with the support of ACCIÓ (Catalonia Trade & Investment; Generalitat de Catalunya) under the Catalonian ERDF operational programme (European Regional Development Fund) 2014-2020. FEB is a researcher from Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol, supported by the Health Department of the Catalan Government (Generalitat de Catalunya). Our laboratory is awarded by the Generalitat de Catalunya as Consolidated Research Groups (ref. 2017-SGR-719, 2017-SGR-301 and 2017-SGR-483).

Published
2019

3. Glioblastoma Bystander Cell Therapy: Improvements in Treatment and Insights into the Therapy Mechanisms

Author

Lourdes Sánchez-Cid, Nuria Rubio, Carolina Soler-Botija, José Becerra, Carolina Nogueira de Moraes, Olaia F. Vila, Sara Ramos-Romero, Marta Guerra-Rebollo, Jerónimo Blanco, Cristina Alcoholado, Cristina Garrido, Óscar Meca-Cortés, Ministerio de Economía y Competitividad (España), Catalonian Institute for Advanced Chemistry (IQAC-CSIC), Biomaterials and Nanomedicine (CIBER-BBN), Universidade Estadual Paulista (Unesp), Biomedical Research Institute of Málaga (IBIMA), Health Science Research Institute Germans Trias i Pujol, Carlos III Health Institute, Columbia University, University of Barcelona, and Málaga

Subjects
0301 basic medicine, Cancer Research, Cells, Therapeutic Procedure, lcsh:RC254-282, Article, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, in vivo glioblastoma model, Neoplasms, Bystander effect, glioblastoma bystander therapy, Cytotoxic T cell, Bioluminescence imaging, Medicine, Pharmacology (medical), clarity, mesenchymal stem cell, HVS-thymidine kinase, Mesenchymal Stromal Cells, business.industry, Mesenchymal stem cell, Extracellular vesicle, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, bioluminescence, Tumor Debulking, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, transparent brain, extracellular vesicle, cell therapy, business
Abstract

A preclinical model of glioblastoma (GB) bystander cell therapy using human adipose mesenchymal stromal cells (hAMSCs) is used to address the issues of cell availability, quality, and feasibility of tumor cure. We show that a fast proliferating variety of hAMSCs expressing thymidine kinase (TK) has therapeutic capacity equivalent to that of TK-expressing hAMSCs and can be used in a multiple-inoculation procedure to reduce GB tumors to a chronically inhibited state. We also show that up to 25% of unmodified hAMSCs can be tolerated in the therapeutic procedure without reducing efficacy. Moreover, mimicking a clinical situation, tumor debulking previous to cell therapy inhibits GB tumor growth. To understand these striking results at a cellular level, we used a bioluminescence imaging strategy and showed that tumor-implanted therapeutic cells do not proliferate, are unaffected by GCV, and spontaneously decrease to a stable level. Moreover, using the CLARITY procedure for tridimensional visualization of fluorescent cells in transparent brains, we find therapeutic cells forming vascular-like structures that often associate with tumor cells. In vitro experiments show that therapeutic cells exposed to GCV produce cytotoxic extracellular vesicles and suggest that a similar mechanism may be responsible for the in vivo therapeutic effectiveness of TK-expressing hAMSCs. © 2018 The Author(s), This work was funded by the Spanish Ministry of Science and Innovation (MICINN) (grant SAF2015-64927-C2-1-R), CIBER-BBN, CIBER Cardiovascular (grant CB16/11/00403), Instituto de Salud Carlos III, Red Temática de Investigación Cooperativa TerCel, and the Spanish Ministry of Economy and Competitiveness (MINECO) (grant BIO2015-66266-R). The authors specially thank Dr. Josep Roca from Delfos hospital (Dr. Roca i Noguera aesthetic surgery team) for the kind donation of liposuction for hAMSCs preparation, and to the services of cell culture (Catalonian Institute for Advanced Chemistry-Spanish National Research Council [IQAC-CISC]), animal care (IQAC-CSIC), cell sorting (Scientific and Technological Centers [CCiT]-University of Barcelona), confocal microscopy (CCiT-University of Barcelona), and Central Services for Research Support (SCAI) at the University of Málaga for their technician and specialized support.

Published
2018

4. Acoustic neuroma risk in relation to mobile telephone use: results of the INTERPHONE international case-control study

Author

L. Montestruq, Gabriele Berg-Beckhoff, Anthony J. Swerdlow, N Yamaguchi, Maria Blettner, Joachim Schüz, Neil Pearce, Louise Nadon, Anna Lahkola, C. Johansen, Daniel Krewski, Bruce K. Armstrong, Anne-Sophie Evrard, Tore Tynes, Monika Moissonnier, J Siemiatycki, Ivano Iavarone, Anders Ahlbom, Avital Jarus-Hakak, Martine Vrijheid, M. Bernard, K. G. Blaasaas, Alistair Woodward, S. J. Hepworth, Salminen T, Isabelle Deltour, J Brown, Elisabeth Cardis, Martine Hours, Angela Chetrit, Päivi Kurttio, Patricia A. McKinney, Sigrid Lönn, Maria Feychting, Lars Klaeboe, Siegal Sadetzki, Brigitte Schlehofer, Helle Collatz Christensen, Toru Takebayashi, Interphone Study Grp, Susanna Lagorio, Anssi Auvinen, G.G. Giles, Angus Cook, M. M McBride, Minouk J. Schoemaker, Marie-Élise Parent, Kenneth Muir, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), International Agency for Cancer Research (IACR), IMIM-Hospital del Mar, Generalitat de Catalunya, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Sydney Cancer Centre and School of Public Health, The University of Sydney, Cancer Epidemiology Centre, The Cancer Council Victoria, School of Public Health and Hospital Research Center, Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Cancer Research Centre, BC Cancer Agency (BCCRC), Danish Cancer Society, Institute of Cancer Epidemiology, Radiation and Nuclear Safety Authority [Helsinki] (STUK), Département Transport, Santé, Sécurité (IFSTTAR/TS2), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Lyon, Institute of Medical Biostatistics, Epidemiology and Informatics, Johannes Gutenberg - Universität Mainz (JGU), Department of Epidemiology and International Public Health, Universität Bielefeld = Bielefeld University-Faculty of Public Health, Unit of Environmental Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Cancer & Radiation Epidemiology Unit, Gertner Institute, Chaim Sheba Medical Center, National Centre for Epidemiology Surveillance and Health Promotion, National Institute of Health, Department of Preventive Medicine and Public Health, University School of Medicine, Department of Public Health, University of Otago [Dunedin, Nouvelle-Zélande], Norwegian Radiation Protection Authority, The Cancer Registry of Norway, Norwegian Armed Forces Medical Services, The Institute of Environmental Medicine [Stockholm] (IMM), Karolinska Institutet [Stockholm], University of Leeds, The Health Science Research Institute, University of Warwick [Coventry], Institute of Cancer Research, Institute of cancer research, Center for Research in Environmental Epidemiology (CREAL), Universitat Pompeu Fabra [Barcelona] (UPF)-Catalunya ministerio de salud, This work was supported by funding from the European Fifth Framework Program, ‘Quality of Life and Management of Living Resources’ (contract QLK4-CT-1999901563) and the International Union against Cancer (UICC). The UICC received funds for this purpose from the Mobile Manufacturers’ Forum and GSM Association. Provision of funds to the INTERPHONE study investigators via the UICC was governed by agreements that guaranteed INTERPHONE's complete scientific independence. The terms of these agreements are publicly available at http://www.iarc.fr/en/research-groups/RAD/RCAd.html.The Australian centre was supported by the Australian National Health and Medical Research Council (EME Grant 219129) with funds originally derived from mobile phone service licence fees, Julianne Brown was partly supported by an Australian Postgraduate Award. Cancer Council NSW and Cancer Council Victoria provided most of the infrastructure for the project in Australia.The Canadian centres in Ottawa/Vancouver were supported by a university–industry partnership grant from the Canadian Institutes of Health Research (CIHR), the latter including partial support from the Canadian Wireless Telecommunications Association. The CIHR university–industry partnerships program also includes provisions that ensure complete scientific independence of the investigators. D. Krewski is the Natural Sciences and Engineering Research Council of Canada Chair in Risk Science at the University of Ottawa.The Canada – Montreal study was primarily funded by a grant from the Canadian Institutes of Health Research (project 15 MOP-42525). Additionally, Dr Siemiatycki's research team was partly funded by the Canada Research Chair programme and by the Guzzo-CRS Chair in Environment and Cancer. Dr Parent had a salary award from the Fonds de la recherche en santé du Québec.Additional funding for the study in France was provided by l’Association pour la Recherche sur le Cancer (ARC) [Contrat No. 5142] and three network operators (Orange, SFR, Bouygues Télécom). The funds provided by the operators represented 5% of the total cost of the French study and were governed by contracts guaranteeing the complete scientific independence of the investigators.The Finnish Interphone study received additional national funding from Emil Aaltonen Foundation and Academy of Finland (Grant No. 80921).The German Interphone study received additional national funding from the 'Deutsches Mobilfunkforschungsprogramm [German Mobile Phone Research Program]' of the German Federal Ministry of Environment, Nuclear Safety, and Nature Protection, the Ministry of Environment and Traffic of the state of Baden-Württemberg, the Ministry of Environment of the state of North Rhine-Westphalia, and the MAIFOR Programme of the University of Mainz.The Japanese Interphone study was fully funded by the Ministry of Internal Affairs and Communications of Japan.Funding in New Zealand for this project was provided by the Health Research Council of New Zealand, the Cancer Society of New Zealand, the Wellington Medical Research Foundation, the Hawke's Bay Medical Research Foundation and the Waikato Medical Research Foundation.The Swedish centre was additionally supported by the Swedish Research Council and the Swedish Cancer Society.The UK North study received additional funding from the Health and Safety Executive, the Department of Health, the Mobile Telecommunications, Health and Research (MTHR) program, and the Scottish Executive. The University of Leeds received some financial support on behalf of the 4 centres of the ‘UK North Study’ from the UK Network Operators (O2, Orange, T-Mobile, Vodafone, ‘3’) under legal signed contractual agreements which guaranteed complete independence for the scientific investigators.The Southeast England Centre wishes to acknowledge additional funding from the Mobile Telecommunications, Health and Research (MTHR) programme. The views expressed in this publication are those of the authors and not necessarily of the funders., and The INTERPHONE Study Group

Subjects
Male, Cancer Research, MESH: Neoplasms, Radiation-Induced, Neoplasms, Radiation-Induced, Epidemiology, MESH: Electromagnetic Fields, Decile, MESH: Glioma, 0302 clinical medicine, Risk Factors, Phone, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Meningeal Neoplasms, Odds Ratio, Medicine, Mobile phones, MESH: Middle Aged, Brain Neoplasms, Brain tumour, Glioma, Neuroma, Acoustic, MESH: Follow-Up Studies, Middle Aged, Prognosis, MESH: Case-Control Studies, 3. Good health, Survival Rate, Oncology, Reporting bias, 030220 oncology & carcinogenesis, Censoring (clinical trials), MESH: Brain Neoplasms, Female, Adult, MESH: Survival Rate, Acoustic neuroma, Radiofrequency electromagnetic fields, MESH: Prognosis, MESH: International Agencies, 03 medical and health sciences, Electromagnetic Fields, Vestibular schwannoma, Humans, MESH: Humans, business.industry, International Agencies, MESH: Adult, Odds ratio, medicine.disease, MESH: Meningeal Neoplasms, Confidence interval, MESH: Male, MESH: Odds Ratio, MESH: Cellular Phone, Mobile phone, Case-Control Studies, business, MESH: Female, Cell Phone, 030217 neurology & neurosurgery, Follow-Up Studies, Demography, MESH: Neuroma, Acoustic
Abstract

Background: The rapid increase in mobile telephone use has generated concern about possible health risks of radiofrequency electromagnetic fields from these devices. Methods: A case-control study of 1105 patients with newly diagnosed acoustic neuroma (vestibular schwannoma) and 2145 controls was conducted in 13 countries using a common protocol. Past mobile phone use was assessed by personal interview. In the primary analysis, exposure time was censored at one year before the reference date (date of diagnosis for cases and date of diagnosis of the matched case for controls); analyses censoring exposure at five years before the reference date were also done to allow for a possible longer latent period. Results: The odds ratio (OR) of acoustic neuroma with ever having been a regular mobile phone user was 0.85 (95% confidence interval 0.69-1.04). The OR for >= 10 years after first regular mobile phone use was 0.76 (0.52-1.11). There was no trend of increasing ORs with increasing cumulative call time or cumulative number of calls, with the lowest OR (0.48 (0.30-0.78)) observed in the 9th decile of cumulative call time. In the 10th decile (>= 1640 h) of cumulative call time, the OR was 1.32 (0.88-1.97); there were, however, implausible values of reported use in those with >= 1640 h of accumulated mobile phone use. With censoring at 5 years before the reference date the OR for >= 10 years after first regular mobile phone use was 0.83 (0.58-1.19) and for >= 1640 h of cumulative call time it was 2.79(1.51-5.16). but again with no trend in the lower nine deciles and with the lowest OR in the 9th decile. In general, ORs were not greater in subjects who reported usual phone use on the same side of the head as their tumour than in those who reported it on the opposite side, but it was greater in those in the 10th decile of cumulative hours of use. Conclusions: There was no increase in risk of acoustic neuroma with ever regular use of a mobile phone or for users who began regular use 10 years or more before the reference date. Elevated odds ratios observed at the highest level of cumulative call time could be due to chance, reporting bias or a causal effect. As acoustic neuroma is usually a slowly growing tumour, the interval between introduction of mobile phones and occurrence of the tumour might have been too short to observe an effect, if there is one. (C) 2011 Elsevier Ltd. All rights reserved.

Published
2011
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