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Canadas-Garre M.,Institute Investigacion Biosanitaria Of Granada | Fernandez-Escamilla A.,CSIC - Experimental Station of El Zaidin | Fernandez-Ballester G.,University Miguel Hernandez | Becerra-Massare P.,UGC Anatomia Patologica | And 3 more authors.
Endocrine Practice | Year: 2014

Objective: BRAF mutations are the most common genetic alteration found in papillary thyroid carcinoma (PTC). Approximately, 90% correspond to BRAFV600E, although other less common BRAF mutations have been described. The aim of this study was to describe a new mutation on BRAF gene discovered on the previous thyroid cytology of a patient diagnosed with a follicular variant of PTC (FV-PTC). Methods: The mutation was identified by independent cloning of the 2 alleles and direct sequencing in the previous cytology and tumor tissue samples from a patient diagnosed with FV-PTC. To elucidate the effect of the mutation on the structure and hence on the activating mechanism of the protein, the structures of BRAFI599Ins, BRAFT599Ins, BRAF V599Ins and BRAFV600E were modeled by using the reconstructed wild-type BRAF (BRAFWT) crystal structure. Results: The novel mutation in BRAF consisted in the in-frame insertion of 3 nucleotides (TAA) after nucleotide 1795, resulting in the incorporation of an extra isoleucine residue at position 599 (BRAFI599Ins) of the protein. The structural comparison of BRAFI599Ins, BRAFT599Ins, BRAFV599Ins with BRAF WT, and BRAFV600E models revealed that the overall shape of the kinase was conserved in the protein produced by this novel mutation, except for the displacement of the activation loop (A-loop), as a direct consequence of the increase in loop size, and the exposition of 1 of the 2 residues involved in BRAF activation (T599), probably facilitating its phosphorylation. Conclusion: BRAFI599Ins mutation constitutes a new BRAF mutation affecting the length of the A-loop, which most likely facilitates BRAF activation by altering the A-loop conformation. © 2014 AACE. Source


Ocana-Riola R.,Campus Universitario Of Cartuja | Ocana-Riola R.,Institute Investigacion Biosanitaria Of Granada
Statistics in Biosciences | Year: 2016

Statistics plays a crucial role in research, planning and decision-making in the health sciences. Progress in technologies and continued research in computational statistics has enabled us to implement sophisticated mathematical models within software that are handled by non-statistician researchers. As a result, over the last decades, medical journals have published a host of papers that use some novel statistical method. The aim of this paper is to present a review on how the statistical methods are being applied in the construction of scientific knowledge in health sciences, as well as, to propose some improvement actions. From the early twentieth century, there has been a remarkable surge in scientific evidence alerting on the errors that many non-statistician researchers were making in applying statistical methods. Today, several studies continue showing that a large percentage of articles published in high-impact factor journals contain errors in data analysis or interpretation of results, with the ensuing repercussions on the validity and efficiency of the research conducted. Scientific community should reflect on the causes that have led to this situation, the consequences to the advancement of scientific knowledge and the solutions to this problem. © 2016 International Chinese Statistical Association Source


Gatta G.,Evaluative Epidemiology Unit | Botta L.,Evaluative Epidemiology Unit | Rossi S.,Centro Nazionale Of Epidemiologia | Aareleid T.,National Institute for Health Development | And 19 more authors.
The Lancet Oncology | Year: 2014

Background: Survival and cure rates for childhood cancers in Europe have greatly improved over the past 40 years and are mostly good, although not in all European countries. The EUROCARE-5 survival study estimates survival of children diagnosed with cancer between 2000 and 2007, assesses whether survival differences among European countries have changed, and investigates changes from 1999 to 2007. Methods: We analysed survival data for 157499 children (age 0-14 years) diagnosed between Jan 1, 1978 and Dec 31, 2007. They came from 74 population-based cancer registries in 29 countries. We calculated observed, country-weighted 1-year, 3-year, and 5-year survival for major cancers and all cancers combined. For comparison between countries, we used the corrected group prognosis method to provide survival probabilities adjusted for multiple confounders (sex, age, period of diagnosis, and, for all cancers combined without CNS cancers, casemix). Age-adjusted survival differences by area and calendar period were calculated with period analysis and were given for all cancers combined and the major cancers. Findings: We analysed 59579 cases. For all cancers combined for children diagnosed in 2000-07, 1-year survival was 90·6% (95% CI 90·2-90·9), 3-year survival was 81·0 % (95% CI 80·5-81·4), and 5-year survival was 77·9% (95% CI 77·4-78·3). For all cancers combined, 5-year survival rose from 76·1% (74·4-77·7) for 1999-2001, to 79·1% (77·3-80·7) for 2005-07 (hazard ratio 0·973, 95% CI 0·965-0·982, p<0·0001). The greatest improvements were in eastern Europe, where 5-year survival rose from 65·2% (95% CI 63·1-67·3) in 1999-2001, to 70·2% (67·9-72·3) in 2005-07. Europe-wide average yearly change in mortality (hazard ratio) was 0·939 (95% CI 0·919-0·960) for acute lymphoid leukaemia, 0·959 (0·933-0·986) for acute myeloid leukaemia, and 0·940 (0·897-0·984) for non-Hodgkin lymphoma. Mortality for all of Europe did not change significantly for Hodgkin's lymphoma, Burkitt's lymphoma, CNS tumours, neuroblastoma, Wilms' tumour, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Disparities for 5-year survival persisted between countries and regions, ranging from 70% to 82% (for 2005-07). Interpretation: Several reasons might explain persisting inequalities. The lack of health-care resources is probably most important, especially in some eastern European countries with limited drug supply, lack of specialised centres with multidisciplinary teams, delayed diagnosis and treatment, poor management of treatment, and drug toxicity. In the short term, cross-border care and collaborative programmes could help to narrow the survival gaps in Europe. Funding: Italian Ministry of Health, European Commission, Compagnia di San Paolo Foundation. © 2014 Elsevier Ltd. Source


Perez A.,Hospital Universitario Virgen Of Las Nieves | Gonzalez-Manzano S.,University of Salamanca | Jimenez R.,University of Granada | Jimenez R.,Institute Investigacion Biosanitaria Of Granada | And 9 more authors.
Pharmacological Research | Year: 2014

Quercetin exerts vasodilator, antiplatelet and antiproliferative effects and reduces blood pressure, oxidative status and end-organ damage in hypertensive humans and animal models. We hypothesized that oral quercetin might induce vasodilator effects in humans and that they might be related to the deconjugation of quercetin-3-O-glucuronide (Q3GA). Design: double blind, randomized, placebo-controlled trial. Fifteen healthy volunteers (26 ± 5 years, 6 female) were given a capsule containing placebo, 200 or 400 mg of quercetin in random order in three consecutive weeks. At 2 h a dose-dependent increase in Q3GA was observed in plasma (∼0.4 and 1 μM for 200 and 400 mg, respectively) with minor levels of quercetin and isorhamnetin. No changes were observed in blood pressure. At 5 h quercetin induced and increase in brachial arterial diameter that correlated with the product of the levels of Q3GA by the plasma glucuronidase activity. There was an increase in urinary levels of glutathione but there was no increase in nitrites plus nitrates. Quercetin and isorhamnetin also relaxed human umbilical arteries in vitro while Q3GA was without effect. In conclusions, quercetin exerts acute vasodilator effects in vivo in normotensive, normocholesterolemic human subjects. These results are consistent with the effects being due to the deconjugation of the metabolite Q3GA. © 2014 Elsevier Ltd. Source


Ocana-Riola R.,Campus Universitario Of Cartuja | Ocana-Riola R.,Institute Investigacion Biosanitaria Of Granada | Blanco-Reina E.,University of Malaga | Moreno-Navarro E.,Campus Universitario Of Cartuja | And 2 more authors.
Journal of Stroke and Cerebrovascular Diseases | Year: 2014

Background: The aim of this article is to evaluate the age-period-cohort effects on mortality from cerebrovascular disease in Andalusia (southern Spain) as a whole and in each of its 8 provinces during the period 1981-2008.Methods: A population-based ecologic study was conducted. In all, 145,867 deaths were analyzed for individuals between the ages of 15 and 84 years who died in Andalusia in the period of study. A nonlinear regression model was estimated for each gender group and geographic area. The effects of age, year of death, and birth cohort were parameterized using spline smoothing functions.Results: There is an upward trend in mortality from the age of 25 years. The risk of death was downward for cohorts born after 1896, decreasing after 1970 with steep slope. The analysis of the period effect showed that death rate first declined from 1981 to 1995 and then increased between 1995 and 2000, only to decrease again until 2008.Conclusions: There is a similar age-period-cohort effect on male and female mortality from cerebrovascular disease in all the provinces of Andalusia and for Andalusia as a whole. A significant reduction of male and female mortality has been observed during the last decade. © 2014 National Stroke Association. Source

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