Biosketch Lara Nonell

Lara Nonell

laranonell@vhio.net

Lloc actual

Cap de la Unitat de Bioinformàtica
Professor associat, Departament de Biociències, Universitat de Vic – Universitat Central de Catalunya

Formació acadèmica

Llicenciat en Matemàtiques, Universitat Autònoma de Barcelona (UAB), 1996
Màster en Direcció de Tecnologies de la Informació, La Salle, Universitat Ramon Llull (URL), 2000
Diploma d’Estudis Avançats, Universitat de Barcelona (UB), 2015
Doctorat en Biomedicina, Universitat Pompeu Fabra (UPF), amb la tesi titulada New approaches in omics data modelling, 2019

Àrees de recerca

Implementació i desenvolupament de mètodes bioinformàtics d’última tecnologia i pipelins per donar suport a la investigació del VHIO
Ús de tècniques bioinformàtiques per a la identificació i validació de biomarcadors que s’utilitzaran en el diagnòstic del càncer, amb un èmfasi especial en les tècniques d’aprenentatge automàtic
Aplicació d’algorismes d’integració de dades multiòmiques
Desenvolupament de noves estratègies d’anàlisi bioinformàtica

Publicacions científiques

Pujals M, Mayans C, Bellio C, Méndez O, Greco E, Fasani R, Alemany-Chavarria M, Zamora E, Padilla L, Mitjans F, Nuciforo P, Canals F, Nonell L, Abad M, Saura C, Tabernero J, Villanueva J. RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer. Oncogene. 2023 Aug;42(35):2610-2628.
Zacarías-Fluck MF, Massó-Vallés D, Giuntini F, González-Larreategui Í, Kaur J, Casacuberta-Serra S, Jauset T, Martínez-Martín S, Martín-Fernández G, Serrano Del Pozo E, Foradada L, Grueso J, Nonell L, Beaulieu ME, Whitfield JR, Soucek L. Reducing MYC’s transcriptional footprint unveils a good prognostic gene signature in melanoma. Genes Dev. 2023 Apr 1;37(7-8):303-320.
Martínez-Sabadell A, Morancho B, Rius Ruiz I, Román Alonso M, Ovejero Romero P, Escorihuela M, Chicote I, Palmer HG, Nonell L, Alemany-Chavarria M, Klein C, Bacac M, Arribas J, Arenas EJ. The target antigen determines the mechanism of acquired resistance to T cell-based therapies. Cell Rep. 2022 Oct 18;41(3):111430.
Hernández-Llodrà S, Segalés L, Juanpere N, Marta Lorenzo T, Salido M, Nonell L, David López T, Rodríguez-Vida A, Bellmunt J, Fumadó L, Cecchini L, Lloreta- Trull J. SPOP and CHD1 alterations in prostate cancer: Relationship with PTEN loss, tumor grade, perineural infiltration, and PSA recurrence. Prostate. 2021 Sep 17. doi: 10.1002/pros.24218. Epub ahead of print. PMID: 34533858.
Palou-Márquez G, Subirana I, Nonell L, Fernández-Sanlés A, Elosua R. DNA methylation and gene expression integration in cardiovascular disease. Clin Epigenetics. 2021 Apr 9;13(1):75. doi: 10.1186/s13148-021-01064-y. PMID: 33836805; PMCID: PMC8034168.
Martín-Sánchez A, Piñero J, Nonell L, Arnal M, Ribe EM, Nevado-Holgado A, Lovestone S, Sanz F, Furlong LI, Valverde O. Comorbidity between Alzheimer’s disease and major depression: a behavioural and transcriptomic characterization study in mice. Alzheimers Res Ther. 2021 Apr 2;13(1):73. doi: 10.1186/s13195-021-00810-x. PMID: 33795014; PMCID: PMC8017643.
Puiggros A, Blanco G, Muntasell A, Rodríguez-Rivera M, Nonell L, Altadill M, Puigdecanet E, Arnal M, Calvo X, Gimeno E, Abella E, Abrisqueta P, Bosch F, Yélamos J, Ferrer A, López-Botet M, Espinet B. Reduced expansion of CD94/NKG2C<sup>+</sup> NK cells in chronic lymphocytic leukemia and CLL-like monoclonal B-cell lymphocytosis is not related to increased human cytomegalovirus seronegativity or NKG2C deletions. Int J Lab Hematol. 2021 Oct;43(5):1032-1040. doi: 10.1111/ijlh.13494. Epub 2021 Feb 22. PMID: 33615729.
Gil-Gómez G, Fassan M, Nonell L, Garrido M, Climent M, Anglada R, Iglesias M, Guzzardo V, Borga C, Grande L, de Bolós C, Pera M. miR-24-3p regulates CDX2 during intestinalization of cardiac-type epithelium in a human model of Barrett’s esophagus. Dis Esophagus. 2021 Jul 12;34(7):doab005. doi: 10.1093/dote/doab005. PMID: 33558874.
Blanco G, Puiggros A, Sherry B, Nonell L, Calvo X, Puigdecanet E, Chiu PY, Kieso Y, Ferrer G, Palacios F, Arnal M, Rodríguez-Rivera M, Gimeno E, Abella E, Rai KR, Abrisqueta P, Bosch F, Calon A, Ferrer A, Chiorazzi N, Espinet B. Chronic lymphocytic leukemia-like monoclonal B-cell lymphocytosis exhibits an increased inflammatory signature that is reduced in early-stage chronic lymphocytic leukemia. Exp Hematol. 2021 Mar;95:68-80. doi: 10.1016/j.exphem.2020.12.007. Epub 2021 Jan 7. PMID: 33421548.
Almanza-Aguilera E, Hernáez Á, Corella D, Sanllorente A, Ros E, Portolés O, Valussi J, Estruch R, Coltell O, Subirana I, Canudas S, Razquin C, Blanchart G, Nonell L, Fitó M, Castañer O. Cancer Signaling Transcriptome Is Upregulated in Type 2 Diabetes Mellitus. J Clin Med. 2020 Dec 29;10(1):85. doi: 10.3390/jcm10010085. PMID: 33383630; PMCID: PMC7795776.
García-Colmenero L, González J, Sandoval J, Guillén Y, Diaz-Lagares A, Andrades E, Iglesias A, Nonell L, Pujol RM, Bigas A, Espinosa L, Gallardo F. Epigenetic Silencing of Tumor Suppressor miR-124 Directly Supports STAT3 Activation in Cutaneous T-Cell Lymphoma. Cells. 2020 Dec 15;9(12):2692. doi: 10.3390/cells9122692. PMID: 33333886; PMCID: PMC7765332.
Segura S, Gadea A, Nonell L, Andrades E, Sánchez S, Pujol R, Hernández-Muñoz I, Toll A. Identification of differentially expressed genes in actinic keratosis samples treated with ingenol mebutate gel. PLoS One. 2020 May 15;15(5):e0232146. doi: 10.1371/journal.pone.0232146. PMID: 32413042; PMCID: PMC7228095.
Dégano IR, Camps-Vilaró A, Subirana I, García-Mateo N, Cidad P, Muñoz-Aguayo D, Puigdecanet E, Nonell L, Vila J, Crepaldi FM, de Gonzalo-Calvo D, Llorente-Cortés V, Pérez-García MT, Elosua R, Fitó M, Marrugat J. Association of Circulating microRNAs with Coronary Artery Disease and Usefulness for Reclassification of Healthy Individuals: The REGICOR Study. J Clin Med. 2020 May 9;9(5):1402. doi: 10.3390/jcm9051402. PMID: 32397522; PMCID: PMC7290581.
Almanza-Aguilera E, Hernáez A, Corella D, Aguayo DM, Ros E, Portolés O, Valussi J, Estruch R, Coltell O, Subirana I, Salas-Salvadó J, Ruiz-Canela M, de la Torre R, Nonell L, Fitó M, Castañer O. Transcriptional response to a Mediterranean diet intervention exerts a modulatory effect on neuroinflammation signaling pathway. Nutr Neurosci. 2020 Apr 15:1-10. doi: 10.1080/1028415X.2020.1749334. Epub ahead of print. PMID: 32290787.
Carrillo-Reixach J, Torrens L, Simon-Coma M, Royo L, Domingo-Sàbat M, Abril-Fornaguera J, Akers N, Sala M, Ragull S, Arnal M, Villalmanzo N, Cairo S, Villanueva A, Kappler R, Garrido M, Guerra L, Sábado C, Guillén G, Mallo M, Piñeyro D, Vázquez-Vitali M, Kuchuk O, Mateos ME, Ramírez G, Santamaría ML, Mozo Y, Soriano A, Grotzer M, Branchereau S, de Andoin NG, López-Ibor B, López-Almaraz R, Salinas JA, Torres B, Hernández F, Uriz JJ, Fabre M, Blanco J, Paris C, Bajčiová V, Laureys G, Masnou H, Clos A, Belendez C, Guettier C, Sumoy L, Planas R, Jordà M, Nonell L, Czauderna P, Morland B, Sia D, Losic B, Buendia MA, Sarrias MR, Llovet JM, Armengol C. Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications. J Hepatol. 2020 Aug;73(2):328-341. doi: 10.1016/j.jhep.2020.03.025. Epub 2020 Mar 30. PMID: 32240714.
Bustamante M, Hernandez-Ferrer C, Tewari A, Sarria Y, Harrison GI, Puigdecanet E, Nonell L, Kang W, Friedländer MR, Estivill X, González JR, Nieuwenhuijsen M, Young AR. Dose and time effects of solar-simulated ultraviolet radiation on the in vivo human skin transcriptome. Br J Dermatol. 2020 Jun;182(6):1458-1468. doi: 10.1111/bjd.18527. Epub 2019 Nov 27. PMID: 31529490; PMCID: PMC7318624.
Hardy-Werbin M, Rocha P, Arpi O, Taus Á, Nonell L, Durán X, Villanueva X, Joseph-Pietras D, Nolan L, Danson S, Griffiths R, Lopez-Botet M, Rovira A, Albanell J, Ottensmeier C, Arriola E. Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer. Oncoimmunology. 2019 Mar 27;8(6):e1593810. doi: 10.1080/2162402X.2019.1593810. PMID: 31069160; PMCID: PMC6492977.
de la Oliva J, Larque AB, Marti C, Bodalo-Torruella M, Nonell L, Nadal A, Castillo P, Sieira R, Ferrer A, Garcia-Diez E, Alos L. Oral premalignant lesions of smokers and non-smokers show similar carcinogenic pathways and outcomes. A clinicopathological and molecular comparative analysis. J Oral Pathol Med. 2021 Mar;50(3):280-286. doi: 10.1111/jop.12864. Epub 2019 Jul 9. PMID: 31006144.
García-Díez I, Hernández-Muñoz I, Hernández-Ruiz E, Nonell L, Puigdecanet E, Bódalo-Torruella M, Andrades E, Pujol RM, Toll A. Transcriptome and cytogenetic profiling analysis of matched in situ/invasive cutaneous squamous cell carcinomas from immunocompetent patients. Genes Chromosomes Cancer. 2019 Mar;58(3):164-174. doi: 10.1002/gcc.22712. Epub 2019 Jan 7. PMID: 30474248.
Pascual-Reguant L, Blanco E, Galan S, Le Dily F, Cuartero Y, Serra-Bardenys G, Di Carlo V, Iturbide A, Cebrià-Costa JP, Nonell L, de Herreros AG, Di Croce L, Marti-Renom MA, Peiró S. Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains. Nat Commun. 2018 Aug 24;9(1):3420. doi: 10.1038/s41467-018-05912-z. PMID: 30143639; PMCID: PMC6109041.
De-Ugarte L, Serra-Vinardell J, Nonell L, Balcells S, Arnal M, Nogues X, Mellibovsky L, Grinberg D, Diez-Perez A, Garcia-Giralt N. Expression profiling of microRNAs in human bone tissue from postmenopausal women. Hum Cell. 2018 Jan;31(1):33-41. doi: 10.1007/s13577-017-0181-y. Epub 2017 Sep 20. PMID: 28933035.
Bustamante M, Hernandez-Ferrer C, Sarria Y, Harrison GI, Nonell L, Kang W, Friedländer MR, Estivill X, González JR, Nieuwenhuijsen M, Young AR. The acute effects of ultraviolet radiation on the blood transcriptome are independent of plasma 25OHD<sub>3</sub>. Environ Res. 2017 Nov;159:239-248. doi: 10.1016/j.envres.2017.07.045. Epub 2017 Sep 18. PMID: 28822308.
Garcia-Elias A, Alloza L, Puigdecanet E, Nonell L, Tajes M, Curado J, Enjuanes C, Díaz O, Bruguera J, Martí-Almor J, Comín-Colet J, Benito B. Defining quantification methods and optimizing protocols for microarray hybridization of circulating microRNAs. Sci Rep. 2017 Aug 10;7(1):7725. doi: 10.1038/s41598-017-08134-3. PMID: 28798363; PMCID: PMC5552704.
Companioni O, Sanz-Anquela JM, Pardo ML, Puigdecanet E, Nonell L, García N, Parra Blanco V, López C, Andreu V, Cuatrecasas M, Garmendia M, Gisbert JP, Gonzalez CA, Sala N. Gene expression study and pathway analysis of histological subtypes of intestinal metaplasia that progress to gastric cancer. PLoS One. 2017 Apr 25;12(4):e0176043. doi: 10.1371/journal.pone.0176043. PMID: 28441455; PMCID: PMC5404762.
Giménez-Arnau A, Curto-Barredo L, Nonell L, Puigdecanet E, Yelamos J, Gimeno R, Rüberg S, Santamaria-Babi L, Pujol RM. Transcriptome analysis of severely active chronic spontaneous urticaria shows an overall immunological skin involvement. Allergy. 2017 Nov;72(11):1778-1790. doi: 10.1111/all.13183. Epub 2017 May 26. PMID: 28407332.
Colomo L, Vazquez I, Papaleo N, Espinet B, Ferrer A, Franco C, Comerma L, Hernandez S, Calvo X, Salar A, Climent F, Mate JL, Forcada P, Mozos A, Nonell L, Martinez A, Carrio A, Costa D, Dlouhy I, Salaverria I, Martin-Subero JI, Lopez-Guillermo A, Valera A, Campo E; Grup per l’Estudi dels Limfomes de Catalunya i Balears (GELCAB). LMO2-negative Expression Predicts the Presence of MYC Translocations in Aggressive B-Cell Lymphomas. Am J Surg Pathol. 2017 Jul;41(7):877-886. doi: 10.1097/PAS.0000000000000839. Erratum in: Am J Surg Pathol. 2019 Mar;43(3):434. PMID: 28288039.
Alonso S, Mayol X, Nonell L, Salvans S, Pascual M, Pera M; Colorectal Cancer Research Group (Hospital del Mar Medical Research Institute). Peripheral blood leucocytes show differential expression of tumour progression-related genes in colorectal cancer patients who have a postoperative intra-abdominal infection: a prospective matched cohort study. Colorectal Dis. 2017 May;19(5):O115-O125. doi: 10.1111/codi.13635. PMID: 28214365.
Lloreta J, Font-Tello A, Juanpere N, Frances A, Lorenzo M, Nonell L, de Muga S, Vázquez I, Cecchini L, Hernández-Llodrà S. FOXO1 down-regulation is associated with worse outcome in bladder cancer and adds significant prognostic information to p53 overexpression. Hum Pathol. 2017 Apr;62:222-231. doi: 10.1016/j.humpath.2016.12.022. Epub 2017 Jan 11. PMID: 28087474.
Nomdedéu JF, Puigdecanet E, Bussaglia E, Hernández JJ, Carricondo M, Estivill C, Martí-Tutusaus JM, Tormo M, Zamora L, Serrano E, Perea G, de Llano MPQ, García A, Sánchez-Ortega I, Ribera JM, Nonell L, Aventin A, Solé F, Brunet MS, Sierra J. Feasibility of the AML profiler (Skyline™ Array) for patient risk stratification in a multicentre trial: a preliminary comparison with the conventional approach. Hematol Oncol. 2017 Dec;35(4):778-788. doi: 10.1002/hon.2304. Epub 2016 May 3. PMID: 27140599.
Nicolle D, Fabre M, Simon-Coma M, Gorse A, Kappler R, Nonell L, Mallo M, Haidar H, Déas O, Mussini C, Guettier C, Redon MJ, Brugières L, Ghigna MR, Fadel E, Galmiche-Rolland L, Chardot C, Judde JG, Armengol C, Branchereau S, Cairo S. Patient-derived mouse xenografts from pediatric liver cancer predict tumor recurrence and advise clinical management. Hepatology. 2016 Oct;64(4):1121-35. doi: 10.1002/hep.28621. Epub 2016 Jun 16. PMID: 27115099.
Pavlovic M, Arnal-Estapé A, Rojo F, Bellmunt A, Tarragona M, Guiu M, Planet E, Garcia-Albéniz X, Morales M, Urosevic J, Gawrzak S, Rovira A, Prat A, Nonell L, Lluch A, Jean-Mairet J, Coleman R, Albanell J, Gomis RR. Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis. J Natl Cancer Inst. 2015 Sep 15;107(12):djv256. doi: 10.1093/jnci/djv256. PMID: 26376684; PMCID: PMC4681582.
Ortega FJ, Mercader JM, Moreno-Navarrete JM, Nonell L, Puigdecanet E, Rodriquez-Hermosa JI, Rovira O, Xifra G, Guerra E, Moreno M, Mayas D, Moreno- Castellanos N, Fernández-Formoso JA, Ricart W, Tinahones FJ, Torrents D, Malagón MM, Fernández-Real JM. Surgery-Induced Weight Loss Is Associated With the Downregulation of Genes Targeted by MicroRNAs in Adipose Tissue. J Clin Endocrinol Metab. 2015 Nov;100(11):E1467-76. doi: 10.1210/jc.2015-2357. Epub 2015 Aug 7. PMID: 26252355.
de la Chica RA, de Lara À, Nonell L, Clusellas N. Structural chromosome rearrangements in prenatal diagnosis: results from a Spanish database. Eur J Obstet Gynecol Reprod Biol. 2015 Nov;194:252-4. doi: 10.1016/j.ejogrb.2015.07.004. Epub 2015 Jul 17. PMID: 26227736.
Gallardo F, Padrón A, Garcia-Carbonell R, Rius C, González-Perez A, Arumí-Uria M, Iglesias M, Nonell L, Bellosillo B, Segura S, Pujol RM, Lopez-Bigas N, Bertran J, Bigas A, Espinosa L. Cytoplasmic accumulation of NCoR in malignant melanoma: consequences of altered gene repression and prognostic significance.Oncotarget. 2015 Apr 20;6(11):9284-94. doi: 10.18632/oncotarget.3252. PMID: 25823659; PMCID: PMC4496217.
Sandoval J, Díaz-Lagares A, Salgado R, Servitje O, Climent F, Ortiz-Romero PL, Pérez-Ferriols A, Garcia-Muret MP, Estrach T, Garcia M, Nonell L, Esteller M, Pujol RM, Espinet B, Gallardo F. MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma. J Invest Dermatol. 2015 Apr;135(4):1128-1137. doi: 10.1038/jid.2014.487. Epub 2014 Nov 18. PMID: 25405321.
Nadal R, Salido M, Nonell L, Rodríguez-Rivera M, Puigdecanet E, Garcia-Puche JL, Macià M, Corominas JM, Serrano MJ, Lorente JA, Solé F. Combined analysis of copy number alterations by single-nucleotide polymorphism array and MYC status in non-metastatic breast cancer patients: comparison according to the circulating tumor cell status. Tumour Biol. 2015 Feb;36(2):711-8. doi: 10.1007/s13277-014-2668-4. Epub 2014 Oct 7. PMID: 25286758.
Espinet B, Ferrer A, Bellosillo B, Nonell L, Salar A, Fernández-Rodríguez C, Puigdecanet E, Gimeno J, Garcia-Garcia M, Vela MC, Luño E, Collado R, Navarro JT, de la Banda E, Abrisqueta P, Arenillas L, Serrano C, Lloreta J, Miñana B, Cerutti A, Florensa L, Orfao A, Sanz F, Solé F, Dominguez-Sola D, Serrano S. Distinction between asymptomatic monoclonal B-cell lymphocytosis with cyclin D1 overexpression and mantle cell lymphoma: from molecular profiling to flow cytometry. Clin Cancer Res. 2014 Feb 15;20(4):1007-19. doi: 10.1158/1078-0432.CCR-13-1077. Epub 2013 Dec 18. PMID: 24352646; PMCID: PMC4488901.
Rojo F, Domingo L, Sala M, Zazo S, Chamizo C, Menendez S, Arpi O, Corominas JM, Bragado R, Servitja S, Tusquets I, Nonell L, Macià F, Martínez J, Rovira A, Albanell J, Castells X. Gene expression profiling in true interval breast cancer reveals overactivation of the mTOR signaling pathway. Cancer Epidemiol Biomarkers Prev. 2014 Feb;23(2):288-99. doi: 10.1158/1055-9965.EPI-13-0761. Epub 2013 Dec 17. PMID: 24347552.
Castañer O, Corella D, Covas MI, Sorlí JV, Subirana I, Flores-Mateo G, Nonell L, Bulló M, de la Torre R, Portolés O, Fitó M; PREDIMED study investigators. In vivo transcriptomic profile after a Mediterranean diet in high-cardiovascular risk patients: a randomized controlled trial. Am J Clin Nutr. 2013 Sep;98(3):845-53. doi: 10.3945/ajcn.113.060582. Epub 2013 Jul 31. PMID: 23902780.
Prat-Vidal C, Gálvez-Montón C, Nonell L, Puigdecanet E, Astier L, Solé F, Bayes-Genis A. Identification of temporal and region-specific myocardial gene expression patterns in response to infarction in swine. PLoS One. 2013;8(1):e54785. doi: 10.1371/journal.pone.0054785. Epub 2013 Jan 25. PMID: 23372767; PMCID: PMC3556027.
Agell L, Hernández S, Nonell L, Lorenzo M, Puigdecanet E, de Muga S, Juanpere N, Bermudo R, Fernández PL, Lorente JA, Serrano S, Lloreta J. A 12-gene expression signature is associated with aggressive histological in prostate cancer: SEC14L1 and TCEB1 genes are potential markers of progression. Am J Pathol. 2012 Nov;181(5):1585-94. doi: 10.1016/j.ajpath.2012.08.005. Erratum in: Am J Pathol. 2013 Feb;182(2):610. PMID: 23083832.
Puiggros A, Puigdecanet E, Salido M, Ferrer A, Abella E, Gimeno E, Nonell L, Herranz MJ, Galván AB, Rodríguez-Rivera M, Melero C, Pairet S, Bellosillo B, Serrano S, Florensa L, Solé F, Espinet B. Genomic arrays in chronic lymphocytic leukemia routine clinical practice: are we ready to substitute conventional cytogenetics and fluorescence in situ hybridization techniques? Leuk Lymphoma. 2013 May;54(5):986-95. doi: 10.3109/10428194.2012.731598. Epub 2012 Oct 16. PMID: 22994157.
Malhotra S, Bustamante MF, Pérez-Miralles F, Rio J, Ruiz de Villa MC, Vegas E, Nonell L, Deisenhammer F, Fissolo N, Nurtdinov RN, Montalban X, Comabella M. Search for specific biomarkers of IFNβ bioactivity in patients with multiple sclerosis. PLoS One. 2011;6(8):e23634. doi: 10.1371/journal.pone.0023634. Epub 2011 Aug 23. PMID: 21886806; PMCID: PMC3160307.
Comabella M, Lünemann JD, Río J, Sánchez A, López C, Julià E, Fernández M, Nonell L, Camiña-Tato M, Deisenhammer F, Caballero E, Tortola MT, Prinz M, Montalban X, Martin R. A type I interferon signature in monocytes is associated with poor response to interferon-beta in multiple sclerosis. Brain. 2009 Dec;132(Pt 12):3353-65. doi: 10.1093/brain/awp228. PMID: 19741051.
Comabella M, Río J, Espejo C, Ruiz de Villa M, Al-Zayat H, Nos C, Deisenhammer F, Baranzini SE, Nonell L, López C, Julià E, Oksenberg JR, Montalban X. Changes in matrix metalloproteinases and their inhibitors during interferon-beta treatment in multiple sclerosis. Clin Immunol. 2009 Feb;130(2):145-50. doi: 10.1016/j.clim.2008.09.010. Epub 2008 Oct 21. PMID: 18945642.