Papers by Pedro López-romero
MicroRNAs (miRNAs) are 21-24 nucleotide RNA molecules that regulate the translation and stability... more MicroRNAs (miRNAs) are 21-24 nucleotide RNA molecules that regulate the translation and stability of target messenger RNAs. Abnormal miRNA expression is a common feature of diverse cancers. Several previous studies have classified miRNA expression in pancreatic ductal adenocarcinoma (PDAC), although no uniform pattern of miRNA dysregulation has emerged. To clarify these previous findings as well as to set the stage for detailed functional analyses, we performed global miRNA expression profiling of 21 human PDAC cell lines, the most extensive panel studied to date. Overall, 39 miRNAs were found to be dysregulated and have at least twofold or greater differential expression in PDAC cell lines compared to control non-transformed pancreatic ductal cell lines. Several of these miRNAs show comparable dysregulation in first-passage patientderived xenografts. Initial functional analyses demonstrate that enforced expression of miRNAs derived from the miR-200 family and the miR-17-92 cluster, both of which are overexpressed in PDAC cell lines, enhances proliferation. In contrast, inhibition of the miR-200 family, the miR-17-92 cluster, or miR-191 diminishes anchorage independent growth. Consistent with a known role for the miR-200 family in negatively regulating an epithelial-to-mesenchymal transition (EMT), the abundance of these miRNAs correlated positively with E-cadherin expression and negatively with the EMT-associated transcription factor and established miR-200 target ZEB1. Finally, restituted expression of miR-34a, a miRNA whose expression is frequently lost in PDAC cell lines, abrogates growth, demonstrating that the anti-proliferative activity of this miRNA is operative in PDAC. These results, and the widespread availability of PDAC cell lines wherein the aforementioned data were
Arthritis Research & Therapy
Background: The development of autoantibodies in patients with rheumatoid arthritis (RA) has pote... more Background: The development of autoantibodies in patients with rheumatoid arthritis (RA) has potential as a marker of treatment response. This analysis assessed the association of an autoantibody response to carbamylated vimentin (anti-CarbV) and to vimentin modified by citrullination (anti-MCV) with response to treatment and structural damage progression in the phase III study RA-BEGIN. Methods: Data from patients in the modified intent-to-treat population of RA-BEGIN were included for analysis; these patients received methotrexate (MTX), baricitinib 4 mg once daily, or baricitinib plus MTX during the 52-week study period. Endpoints analyzed were clinical response to treatment, assessed using change from baseline (CFB) in Simplified Disease Activity Index (SDAI) and Disease Activity Score for 28-joint count with serum high-sensitivity Creactive protein (DAS28-hsCRP), and structural damage progression, assessed using CFB greater than the smallest detectable change in the van der Heijde-modified Total Sharp Score. The anti-CarbV and anti-MCV isotypes assessed were immunoglobulin (Ig) A, IgG, and IgM. Multivariable mixed-effect models for repeated measures (MMRMs) were used for the longitudinal analysis of treatment response, and multivariable logistic regression models were used for the analysis of structural damage progression at week 52.
P204 Effect of baricitinib on functional impairment in RA patients with moderate disease activity and an inadequate response to conventional DMARDs
Rheumatology
Background In RA, disease activity correlates with physical function and there is a link between ... more Background In RA, disease activity correlates with physical function and there is a link between joint damage and functional disability. In many countries, RA patients with inadequate response (IR) to MTX or other conventional DMARDs (cDMARDs) are not eligible for potentially more effective treatments, such as biologic or targeted synthetic DMARDs (tsDMARDs), unless they have high disease activity (HDA). Thus, managing RA patients with persistent moderate disease activity (MDA) despite cDMARD treatment poses a problem. Baricitinib (BARI) is a tsDMARD approved for the treatment of moderate to severe RA in adults. This post-hoc analysis assessed if RA patients with MDA benefit from improved physical function with BARI treatment to the same extent as patients with HDA. Methods Patients analysed were from the modified intention-to-treat populations in the BARI phase 3 studies RA-BEAM (MTX-IR) and RA-BUILD (cDMARD-IR) with moderate to severe disability (HAQ-Disability Index [HAQ-DI] scor...
Calcified Tissue International
Vertebral fractures (VFx) occur most frequently in the mid-thoracic and thoraco-lumbar regions, w... more Vertebral fractures (VFx) occur most frequently in the mid-thoracic and thoraco-lumbar regions, which experience the highest mechanical loading along the spine. The prevalence and incidence of VFx by their location and severity, and their relationship with bone mineral density (BMD), are seldom reported in randomized clinical trial cohorts. The VERO trial randomized 1360 postmenopausal women with at least two moderate or one severe VFx to receive either teriparatide or risedronate for up to 24 months. In this post hoc analysis, we describe the centrally read distribution and severity of prevalent and incident VFx, and the association of their location with the baseline BMD. At baseline, 21.4% of all evaluable vertebral bodies had a prevalent VFx; most commonly at L1, T12, L2 and T11 (38.5%, 37.4%, 25.3% and 23.5% of patients, respectively). Patients with prevalent VFx only at T12/L1 showed a higher baseline BMD compared to patients with VFx at other levels. At month 24, 100 patients...
Psychotropic Medications and Proton Pump Inhibitors and the Risk of Fractures in the Teriparatide versus Risedronate VERO Clinical Trial
Bone
SATURDAY, 15 JUNE 2019
Background: There have been important changes in the management of RA in the last 20 years, such ... more Background: There have been important changes in the management of RA in the last 20 years, such as T2T strategy or new biologic agents. The potential impact of these therapeutic strategies on important objectives such as intrahospital mortality due to different causes is not known. Objectives: To analyze the incidence and tendency of mortality by different causes (global, cardiovascular, infectious, neoplasm, and others) in patients with RA, in Spain, during the period 1999-2015. Methods: Retrospective cohort study based on the exploitation of the database that collects a minimum basic set of data (MBDS) of all income in patients with RA. Period: 1999 to 2015. We analyzed cases of intrahospital death and the main diagnosis of these cases. The causes of death were identified by the presence of the corresponding ICD 9 codes in the main diagnostic fields. The causes of death in the hospital,
Clinical Rheumatology
The objective of this study was to evaluate structural damage progression based on clinical respo... more The objective of this study was to evaluate structural damage progression based on clinical response in rheumatoid arthritis patients with no or limited prior disease-modifying anti-rheumatic drug treatment receiving the Janus kinase (JAK)1/JAK2 inhibitor baricitinib 4 mg, methotrexate (MTX), or the combination. Data from the phase 3 RA-BEGIN study were analysed post hoc. Proportions of patients with structural damage progression (change from baseline greater than the smallest detectable change in modified total Sharp score) at week 52 were evaluated based on sustained Disease Activity Score for 28-joint count with serum high-sensitivity C-reactive protein (DAS28-hsCRP) ≤ 3.2 or Simplified Disease Activity Index (SDAI) score ≤ 11; no formal statistical comparisons between treatments were performed to test these proportions. Baseline factors associated with risk of structural damage progression, including Clinical Disease Activity Index (CDAI) score, were identified using multivariate analysis. Patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to experience structural damage progression at week 52. In patients achieving these responses, structural damage progression was less likely with baricitinib monotherapy or plus MTX than with MTX monotherapy. In patients not achieving these sustained clinical thresholds, structural damage progression was less likely with baricitinib plus MTX than with either monotherapy. Independent of treatment, baseline factors significantly associated with increased risk of structural damage progression included higher hsCRP and CDAI score, smoking, female sex, and lower body mass index. In conclusion, patients achieving versus not achieving sustained DAS28-hsCRP ≤ 3.2 or SDAI score ≤ 11 were less likely to show structural damage progression, irrespective of treatment.
Serum 25-hydroxy-vitamin D and the risk of fractures in the teriparatide versus risedronate VERO clinical trial
Archives of Osteoporosis
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, Jan 12, 2018
The 2-year, randomized, double-blind, active-controlled fracture endpoint VERO study included pos... more The 2-year, randomized, double-blind, active-controlled fracture endpoint VERO study included postmenopausal women with established osteoporosis, who had at least 2 moderate or 1 severe baseline vertebral fractures (VFx), and bone mineral density (BMD) T-score ≤-1.5. Patients were treated with either s.c. daily teriparatide 20 μg or oral weekly risedronate 35 mg. As previously reported, the risk of new VFx and clinical fractures (a composite of clinical VFx and nonvertebral fragility fractures [NVFFx]) was statistically significantly reduced with teriparatide compared with risedronate. Here we present the prospectively planned subgroup analyses of fracture data across subgroups, which were predefined by the following baseline characteristics: age, number and severity of prevalent VFx, prevalent nonvertebral fractures (NVFx), glucocorticoid use, prior osteoporosis drugs, recent bisphosphonate use, clinical VFx in the year before study entry, and baseline BMD. Heterogeneity of the tre...
Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial
Lancet (London, England), Jan 9, 2017
No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcom... more No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). We enrolled 680 patients in each group. At ...
BMC Musculoskeletal Disorders, 2015
Background: The aim of this study was to evaluate, the existence of a signature of differentially... more Background: The aim of this study was to evaluate, the existence of a signature of differentially expressed microRNAs (miRNAs) during osteogenic differentiation of bone marrow MSCs from OA and healthy donors and to describe their possible implication in joint regeneration through modulation of molecular mechanisms involved in homeostatic control in OA pathophysiology. Methods: Following phenotypic assessment of BM-MSCs obtained from OA diagnosed patients (n = 10) and non-OA (n = 10), total small RNA was isolated after osteogenic induction for 1, 10 and 21 days, miRNA profiles were generated using a commercial expression array of 754 well-characterized miRNAs. MiRNAs, with consistent differential expression were selected for further validation by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. Results: A total of 246 miRNAs were differentially expressed (fold change ≥ ± 2, P ≤0.05) between OA and non-OA BM-MSC samples; these miRNAs showed variable interactions depending on the cell and differentiation status. Two miRNAs, hsa-miR-210 and hsa-miR-335-5p out of 21 used for validation showed a significant downregulated expression during induced osteogenesis. In particular hsa-miR-335-5p, a critical regulator in bone homeostasis, was further studied. hsa-miR-335-5p downregulation in OA-MSCs, as well as their host coding gene, MEST, were also assessed. Conclusions: To our knowledge, this study represents the most comprehensive assessment to date of miRNA expression profiling in BM-MSCs from OA patients and their role during osteogenic differentiation. We describe the existence of a correlation between miR-335-5p expression and OA indicating the putative role of this miRNA in OA features. These findings, may contribute to our understanding of the molecular mechanisms involved in MSCs mediated homeostatic control in OA pathophysiology that could be applicable in future therapeutic approaches.
Circulation, 2013
Background-The effect of β-blockers on infarct size when used in conjunction with primary percuta... more Background-The effect of β-blockers on infarct size when used in conjunction with primary percutaneous coronary intervention is unknown. We hypothesize that metoprolol reduces infarct size when administered early (intravenously before reperfusion). Methods and Results-Patients with Killip class II or less anterior ST-segment-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention within 6 hours of symptoms onset were randomized to receive intravenous metoprolol (n=131) or not (control, n=139) before reperfusion. All patients without contraindications received oral metoprolol within 24 hours. The predefined primary end point was infarct size on magnetic resonance imaging performed 5 to 7 days after STEMI. Magnetic resonance imaging was performed in 220 patients (81%). Mean±SD infarct size by magnetic resonance imaging was smaller after intravenous metoprolol compared with control (25.6±15.3 versus 32.0±22.2 g; adjusted difference, −6.52; 95% confidence interval, −11.39 to −1.78; P=0.012). In patients with pre-percutaneous coronary intervention Thrombolysis in Myocardial Infarction grade 0 to 1 flow, the adjusted treatment difference in infarct size was −8.13 (95% confidence interval, −13.10 to −3.16; P=0.0024). Infarct size estimated by peak and area under the curve creatine kinase release was measured in all study populations and was significantly reduced by intravenous metoprolol. Left ventricular ejection fraction was higher in the intravenous metoprolol group (adjusted difference, 2.67%; 95% confidence interval, 0.09-5.21; P=0.045). The composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours in the intravenous metoprolol and control groups was 7.1% and 12.3%, respectively (P=0.21). Conclusions-In patients with anterior Killip class II or less ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, early intravenous metoprolol before reperfusion reduced infarct size and increased left ventricular ejection fraction with no excess of adverse events during the first 24 hours after STEMI.
BMC Public Health, 2013
Background: The onset of inadequate behaviors leading to the development of risk factors for chro... more Background: The onset of inadequate behaviors leading to the development of risk factors for chronic diseases is known to occur early in life. An effective program for health promotion should therefore focus on children and their environment, as the starting point for behavior development. The overarching objective of the Program SI! (Salud Integral-Comprehensive Health) is to intervene at the school level, to establish and develop life-lasting habits that will help preserving health during adulthood. The Program SI! comprises five consecutive subprograms according to the five stages of education in Spain, the first being in preschoolers. This study aims to evaluate the efficacy of Program SI! to establish and improve lifestyle behaviors in children (preschoolers aged 3-5 years), their parents, and teachers, and also improving the school environment. A secondary objective is to evaluate improvements in cardiovascular health-related markers (anthropometric parameters, blood pressure, and dietary and physical activity patterns) in these same children. Methods/design: 24 public schools from the city of Madrid (Spain) were allocated through stratified randomization to intervention or control. The intervention schools follow the Program SI!, which provides didactic units, emotions cards, healthy tips, and online resources. The intervention schools integrate the Program SI! into their scholar curriculum organized in four complete weeks during each academic year during the 3 years of preschool education. Control schools follow their normal curriculum. Primary outcomes are 1-year, and 3-year changes from baseline of scores for knowledge, attitudes, and habits (KAH) of children, their parents and teachers in regards to a healthy lifestyle. Secondary outcomes are 1-year, and 3-year changes from baseline in clinical and anthropometric parameters of children. Discussion: The Program SI! is a long-term health promotion program starting in 3 years old. It incorporates the traditional areas of intervention (diet and physical activity), introducing additional components such as knowledge of the human body and management of emotions to achieve a comprehensive intervention. The Program SI! is designed to be an effective, sustainable health promotion program for the adoption of healthy behaviors from early in life.
Prediction of Functional Sites in Proteins by Evolutionary Methods
BMC Genomics, 2011
Background: The main research tool for identifying microRNAs involved in specific cellular proces... more Background: The main research tool for identifying microRNAs involved in specific cellular processes is gene expression profiling using microarray technology. Agilent is one of the major producers of microRNA arrays, and microarray data are commonly analyzed by using R and the functions and packages collected in the Bioconductor project. However, an analytical package that integrates the specific characteristics of microRNA Agilent arrays has been lacking. Results: This report presents the new bioinformatic tool AgiMicroRNA for the pre-processing and differential expression analysis of Agilent microRNA array data. The software is implemented in the open-source statistical scripting language R and is integrated in the Bioconductor project (http://www.bioconductor.org) under the GPL license. For the pre-processing of the microRNA signal, AgiMicroRNA incorporates the robust multiarray average algorithm, a method that produces a summary measure of the microRNA expression using a linear model that takes into account the probe affinity effect. To obtain a normalized microRNA signal useful for the statistical analysis, AgiMicroRna offers the possibility of employing either the processed signal estimated by the robust multiarray average algorithm or the processed signal produced by the Agilent image analysis software. The AgiMicroRNA package also incorporates different graphical utilities to assess the quality of the data. AgiMicroRna uses the linear model features implemented in the limma package to assess the differential expression between different experimental conditions and provides links to the miRBase for those microRNAs that have been declared as significant in the statistical analysis. Conclusions: AgiMicroRna is a rational collection of Bioconductor functions that have been wrapped into specific functions in order to ease and systematize the pre-processing and statistical analysis of Agilent microRNA data. The development of this package contributes to the Bioconductor project filling the gap in microRNA array data analysis.
Comparing alternative random regression models to analyse first lactation daily milk yield data in Holstein–Friesian cattle
Livestock Production Science, 2003
Test-day (TD) milk yields from Spanish Holstein cows were analysed in three independent data sets... more Test-day (TD) milk yields from Spanish Holstein cows were analysed in three independent data sets (35 615, 35 209 and 27 272 TD records, respectively) with a set of random regression models. Wilmink and Ali-Schaeffer lactation functions and, Legendre polynomials (RRL) of varying order (up to six coefficients) on additive genetic (AG) and permanent environmental (PE) effects were used. The analysis of the
The Journal of nutrition, 2012
Fiber-rich diets are associated with favorable lipid profiles, but the specific compounds and the... more Fiber-rich diets are associated with favorable lipid profiles, but the specific compounds and the mechanisms behind this effect are yet to be fully understood. Lignans are fiber-related polyphenols that have been associated with lower prevalence of cardiovascular disease. The objective of this study was to investigate the relationship between dietary lignan exposure, measured as the urinary concentration of their metabolites, enterolactone and enterodiol, and serum lipids in a representative sample of U.S. adults. We carried out a cross-sectional analysis of data from 1492 adults who participated in the 1999-2004 NHANES. The mean urinary concentration of enterolignans in U.S. adults was 1.9 μmol/L. The multivariate-adjusted mean differences comparing the highest and lowest enterolignan tertile were 0.06 mmol/L for HDL cholesterol and -0.17 mmol/L for TG (P < 0.05). In spline regression models, we also found an inverse association between serum TG and urinary enterolignan concentr...
Revista española de cardiología, 2011
Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measure that allows us... more Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measure that allows us to assess right ventricular systolic function. TAPSE measurement is common in adults but reference values for children are scarce. Our objective was to establish reference values for TAPSE in Spanish children and to determine the relationship of these values with age and body surface. This prospective study included 405 patients (from newborn to age 18 years, 53% male) referred for assessment of cardiac murmurs. Patients with confirmed cardiac or any other disease were excluded. We collected TAPSE measurements by M-mode echocardiography and recorded anthropometric variables. We analyzed the intra- and interobserver reproducibility of these measurements. Mean TAPSE values were 17.09 ± 5.09 cm with nonsignificant differences between sexes. A curvilinear regression model proved appropriate, with values increasing in proportion to age group, height, weight, body mass index, and body surface...
Rheumatology International, 2010
Soluble interleukin 6 receptor α subunit (sIL-6R) is primarily generated by shedding of the membr... more Soluble interleukin 6 receptor α subunit (sIL-6R) is primarily generated by shedding of the membrane-bound form. This process is influenced by the single nucleotide polymorphism rs8192284 (A>C) resulting in an aspartic acid to alanine substitution (D358A) at the proteolytic cleavage site. The aim of this study was to determine whether plasma levels of sIL6R are influenced by the rs8192284 polymorphism in rheumatoid arthritis patients and to assess the association between plasma sIL-6R levels and disease activity as reflected by anti-CCP status.
Current Topics in Medicinal Chemistry, 2006
To be effective, a designed drug must discriminate successfully the macromolecular target from al... more To be effective, a designed drug must discriminate successfully the macromolecular target from alternative structures present in the organism. The last few years have witnessed the emergence of different computational tools aimed to the understanding and modeling of this process at molecular level. Although still rudimentary, these methods are shaping a coherent approach to help in the design of molecules
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Papers by Pedro López-romero