Nadal, E. (Ernest)
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- Elevated levels of the complement activation product c4d in bronchial fluids for the diagnosis of lung cancer(Public Library of Science, 2015) Pajares, M.J. (María José); Garcia, J. (Javier); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Schmidt, B. (Bernd); Fleischhacker, M. (M.); Nadal, E. (Ernest); Montuenga-Badia, L.M. (Luis M.); Razquin, C. (Cristina); Paz-Ares, L. (Luis); Ajona, D. (Daniel); Pastor, M.D. (María Dolores); Cardenal, F. (F.); Zulueta, J. (Javier)Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort). The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts. C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71-0.94) and 0.67 (95%CI = 0.58-0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts). Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56-0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease.
- KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target(BMC, 2018) Gil-Bazo, I. (Ignacio); Román, M. (Marta); Vicent, S. (Silvestre); Nadal, E. (Ernest); Rolfo, C. (Christian); Baraibar-Argota, I. (Iosune); Lopez, I. (Inés)Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.
- Synthesis and evaluation of new Reissert analogs as HIV-1 RT inhibitors. 2. Benzo[f]quinoline and pyridine derivatives(Informa Healthcare, 1997) Borras-Cuesta, F. (Francisco); Alvarez, E. (E.); Sanmartin-Grijalba, C. (Carmen); Nadal, E. (Ernest); Font, M. (María); Prieto, I. (Inés); Monge, A. (Antonio); Martinez-Irujo, J.J. (Juan José); Sarobe, P. (Pablo); Santiago, E. (Esteban); Ruiz, I. (I); Lasarte, J.J. (Juan José)The synthesis and preliminary evaluation of new benzo[f]quinoline and pyridine derivatives, obtained by application of the Reissert method and its modifications, as HIV-1 RT inhibitors and anti-infectives are presented. The most active products against HIV-1 RT wild type are the ethyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2b, propyl 2-cyano-1,2-dihydrobenzo[f]quinoline-1-carboxylate 2c, and 2-cyano-1-(2'-furoyl)-1,2-dihydrobenzo[f]quinoline 2n, which maintain their activity against the mutant type P236L, resulting inactive against the Y181C type. Using the data previously obtained by our research team for analogous series derived from quinoline as reference, the compounds which have now been obtained present an increase in the cytotoxic character attributable to the introduction of a benzene ring fused with the quinoline base nucleus, as well as a decrease of the activity as HIV-1 RT inhibitors when the quinoline benzenic ring is eliminated.
- Complement factor H is elevated in bronchoalveolar lavage fluid and sputum from patients with lung cancer(American Association for Cancer Research, 2010-08-27) Seijo, L. (Luis); Pajares, M.J. (María José); Garcia, J. (Javier); Pio, R. (Rubén); Lozano, M.D. (María Dolores); Schmidt, B. (Bernd); Fleischhacker, M. (M.); Nadal, E. (Ernest); Corrales, L. (Leticia); Montuenga-Badia, L.M. (Luis M.); Witt, C. (Christian); Ajona, D. (Daniel); Cardenal, F. (F.); Zulueta, J. (Javier)Abstract Background: Cytologic examination of specimens obtained from the respiratory tract is a lung cancer diagnostic procedure with high specificity, but moderate sensitivity. The use of molecular biomarkers may enhance the sensitivity of cytologic examination in the detection of lung cancer. Methods: Complement factor H, a protein secreted by lung cancer cells, was quantified in a series of bronchoalveolar lavage supernatants from lung cancer patients and patients with nonmalignant respiratory diseases. Albumin, total protein content, and hemoglobin were also analyzed. Results were validated in independent sets of bronchoalveolar lavage and sputum supernatants. Results: There was a significantly higher concentration of factor H in bronchoalveolar lavage samples from lung cancer patients. The sensitivity and specificity of the factor H test was 82% and 77%, respectively. These results were validated in an independent set of patients with nearly identical results. Furthermore, 70% and 45% of bronchoalveolar lavage fluids from central and peripheral tumors, respectively, reported as cytologically negative were classified as positive using this marker. Finally, the test was evaluated in a series of sputum supernatants from lung cancer patients and controls. The sensitivity and specificity of the factor H test in this series was 80% and 88%, respectively. Conclusion: Factor H is elevated in bronchoalveolar lavage and sputum from lung cancer patients. Impact: Measurement of molecular biomarkers, such as complement factor H, may be used in the future as an adjunct to cytology in the diagnosis of malignant pulmonary diseases.
- Synthesis and evaluation of new Reissert analogs as HIV-1 reverse transcriptase inhibitors. 1. Quinoline and quinoxaline derivatives(Gordon and Breach, 1997) Merino, I. (Isidro); Cuartero, A. (A); Alberdi, E. (Elena); Borras-Cuesta, F. (Francisco); Fidalgo, M.J. (M. J.); Alvarez, E. (E.); Sanmartin-Grijalba, C. (Carmen); Nadal, E. (Ernest); Font, M. (María); Prieto, I. (Inés); Losa, M.J. (M.J.); Monge, A. (Antonio); Martinez-Irujo, J.J. (Juan José); Sarobe, P. (Pablo); Santiago, E. (Esteban); Ruiz, I. (I); Lasarte, J.J. (Juan José)The synthesis and preliminary evaluation of new quinoline and quinoxaline derivatives (obtained by applying the original Reissert method, conveniently modified) as HIV-1 Reverse Transcriptase (RT) inhibitors are presented in this paper; likewise, the first structure-activity relationships are also proposed. Propyl 2-cyano-1(2H)-quinolin-carboxylate 2e, isopropyl 2-cyano-1 (2H)-quinolincarboxylate 2f, butyl 2-cyano-1 (2H)-quinolincarboxylate 2g and isobutyl 2-cyano-1 (2H)-quinolincarboxylate 2h have been selected as lead compounds. These compounds are active against the HIV-1 RT mutant type P236L (2f, IC50 = 1.2 microM) and present activity as anti-infective agents in HLT41acZ-1IIIB cells, showing no cytotoxicity at the active concentrations.