José Carlos Martínez Ávila

Instituto de Investigación Biosanitaria de Granada

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Alfredo Carrato

Instituto Cajal

Julie Earl

Instituto Cajal

Alberto M. Borobia

Hospital Universitario La Paz

Carmen Guillén‐Ponce

Hospital Universitario Ramón y Cajal

Antonio J. Carcas

Universidad Autónoma de Madrid

Alfonso Sanjuánbenito

Instituto Cajal

José Montáns

Leiden University Medical Center

Núria Malats

Spanish National Cancer Research Centre

Eduardo Lobo

Hospital Universitario Ramón y Cajal

Mercedes Rodríguez-Garrote

Instituto Ramón y Cajal de Investigación Sanitaria

Cooperative Institutions

Universidad Autónoma de Madrid

Instituto de Salud Carlos III

Hospital Universitario La Paz

Instituto Cajal

Hospital Universitario Ramón y Cajal

Centro de Investigación Biomédica en Red

Research Institute Hospital 12 de Octubre

Hospital Universitario 12 De Octubre

Instituto Ramón y Cajal de Investigación Sanitaria

Centro de Investigación Biomédica en Red de Cáncer

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Tocilizumab inhibits progression of joint damage in rheumatoid arthritis irrespective of its anti-inflammatory effects: disassociation of the link between inflammation and destruction

Annals of the Rheumatic Diseases (2011)

Josef S Smolen José Carlos Martínez Ávila Daniel Aletaha

Background Treatment with tumour necrosis factor inhibitors (TNF-i) plus methotrexate (MTX), but not MTX monotherapy alone, inhibits joint damage progression even at higher levels of disease activity. Such disassociation of disease activity and structural damage has not been shown for biological agents other than TNF-i. Objectives To evaluate whether interleukin 6 (IL-6) inhibition with tocilizumab (TCZ) interferes with joint destruction beyond its effects on disease activity. Methods A random 90% sample of data from the (The Tocilizumab Safety and the Prevention of Structural Joint Damage Study) LITHEtrial on active rheumatoid arthritis (RA) despite MTX was used, which compared addition of placebo (n=117) with addition of TCZ (n=414) every 4 weeks. Baseline and 1-year values of clinical and serological variables were correlated with changes to 1 year of the total Genant-modified Sharp score (TGSS) using a Spearman test, and the progression of TGSS, erosion and joint space narrowing (JSN) scores in groups with low and high disease activity were compared for placebo and TCZ (Kruskal–Wallis). Results Baseline variables were similar among the groups. Change of TGSS was lower in patients receiving TCZ than placebo (TCZ: 0.29±0.96; placebo: 0.90±1.92; p=0.0007). In patients receiving placebo, the correlation with TGSS change was significant for baseline scores of the simplified disease activity index (SDAI; r=0.18, p=0.047) and swollen joint count 28 (r=0.22, p=0.019), with similar trends for C-reactive protein. Similar correlations were seen for SDAI, clinical disease activity index, disease activity score 28 at 1 year with x-ray change during that year (r=0.26–0.28, p=0.002–0.006). In contrast, none of the baseline or 1-year variables showed significant correlation with x-ray changes in patients receiving TCZ+MTX, suggesting a disassociation of the link between disease activity and damage by TCZ. Finally, for patients in remission or with low disease activity, progression of TGSS, erosion and JSN was similar among treatment groups (TGSS: placebo, 0.4±1.1; TCZ, 0.2±0.7; p=NS), while for patients with moderate or high disease activity placebo-treated patients progression was significantly greater (TGSS: 1.2±2.2 vs 0.4±1.2; p=0.0009). Conclusions IL-6 inhibition with TCZ plus MTX retards joint damage progression independently of its impact on disease activity. Similar effects have hitherto been reported only for TNF-i. This indicates that the effects of IL-6 inhibition on progression of joint damage in RA are among the most profound currently attainable.

Tocilizumab

10.1136/annrheumdis-2011-200395

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Citations (123)

Prediction models for voriconazole pharmacokinetics based on pharmacogenetics: AN exploratory study in a Spanish population

International Journal of Antimicrobial Agents (2019)

Irene Dapía Irene García-García José Carlos Martínez Ávila Pedro Arias Pedro Ignacio Cardona Guerra

10.1016/j.ijantimicag.2019.06.026

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Citations (20)

Ultra-Deep Targeted Sequencing Does Not Identify MM Patients with Different Prognosis: Results from a Randomized Phase II Clinical Trial

Blood (2016)

Yanira Ruiz‐Heredia Joaquín Martínez‐López José Carlos Martínez Ávila Beatriz Sánchez-Vega Inmaculada Rapado

10.1182/blood.v128.22.2078.2078

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Citations (0)

Radiotherapy in Ledderhose's disease

Reports of Practical Oncology & Radiotherapy (2013)

Miriam García García J.M. Granado Peña S. Villamil C. Fuentes J. M. Martín Martín

10.1016/j.rpor.2013.03.395

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Simple reparameterization to improve convergence in linear mixed models

Acta agriculturae Slovenica (2010)

Gregor Gorjanc Tina Flisar José Carlos Martínez Ávila Luis Alberto García‐Cortés

Slow convergence and mixing are one of the main problems of Markov chain Monte Carlo (McMC) algorithms applied to mixed models in animal breeding. Poor convergence is to a large extent caused by high posterior correlation between variance components and solutions for the levels of associated effects. A simple reparameterization of the conventional model for variance component estimation is presented which improves McMC sampling and provides the same posterior distributions as the conventional model. Reparameterization is based on the rescaling of hierarchical (random) effects in a model, which alleviates posterior correlation. The developed model is compared against the conventional model using several simulated data sets. Results show that presented reparameterization has better behaviour of associated sampling methods and is several times more efficient for the low values of heritability.

Mixed model

Gibbs sampling

10.14720/aas.2010.96.2.14699

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Influence of two variants of CYP450 oxidoreductase on the stable dose of acenocoumarol in a Spanish population

Pharmacogenomics (2017)

Hoi Y. Tong Alberto M. Borobia José Carlos Martínez Ávila Rubin Lubomirov Mario Muñoz

To evaluate the influence of two variants of P450 oxidoreductase (POR), rs2868177 and POR*28, on the stable dosage of acenocoumarol.For this observational, cross-sectional study, patients were undergone stable anticoagulant treatment with acenocoumarol. Univariate and multiple regression analyses were performed to assess the influence of POR polymorphisms.About 340 patients were enrolled. Multiple regression had a coefficient of determination (R2) of 51.5% and an Akaike information criterion of 234.22. The inclusion of POR*28 polymorphisms increased the R2 to 52.0% and reduced the Akaike information criteria to 230.58. The POR*28 heterozygote showed statistical significance in the algorithm.The POR*28 heterozygote appears to be associated with the stable dose of acenocoumarol, but its clinical contribution to the prediction of the dosing of this drug is minimal.

Acenocoumarol

Akaike information criterion

Univariate

Univariate analysis

VKORC1

10.2217/pgs-2017-0021

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Citations (1)

Genetic Deletion of NOD1 Prevents Cardiac Ca2+ Mishandling Induced by Experimental Chronic Kidney Disease

International Journal of Molecular Sciences (2020)

Marta Gil-Fernández José Alberto Navarro‐García Almudena Val‐Blasco Laura González‐Lafuente José Carlos Martínez Ávila

Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response. We evaluated whether the genetic deficiency of Nod1 or Rip2 in mice could prevent cardiac Ca2+ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca2+ dynamics in cardiomyocytes from Wild-type (Wt), Nod1−/− and Rip2−/− sham-operated or nephrectomized mice. Compared with Wt cardiomyocytes, Wt-Nx cells showed an impairment in the properties and kinetics of the intracellular Ca2+ transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca2+ load, together with an increase in diastolic Ca2+ leak. Cardiomyocytes from Nod1−/−-Nx and Rip2−/−-Nx mice showed a significant amelioration in Ca2+ mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca2+ mishandling induced by experimental CKD, unveiling new innate immune targets for the development of innovative therapeutic strategies to reduce cardiac complications in patients with CKD.

NOD1

Calcium in biology

10.3390/ijms21228868

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Citations (5)

Definition of treatment response in rheumatoid arthritis based on the simplified and the clinical disease activity index

Annals of the Rheumatic Diseases (2012)

Daniel Aletaha José Carlos Martínez Ávila Tore K Kvien Josef S Smolen

Background

The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) are established instruments to measure disease activity in rheumatoid arthritis (RA). To date, no validated response definitions for the SDAI and CDAI are available.

Objective

The authors aimed to define minor, moderate and major response criteria for the SDAI.

Methods

The authors used data from two clinical trials on infliximab versus methotrexate in early (ASPIRE) or established (ATTRACT) RA, and identified the three SDAI cutpoints based on the best agreement (by κ statistics) with the American College of Rheumatology (ACR)20/50/70 responses. Cutpoints were then tested for different aspects of validity in the trial datasets and in a Norwegian disease modifying antirheumatic drug prescription dataset (NOR-DMARD).

Results

Based on agreement with the ACR response, the minor, moderate and major responses were identified as SDAI 50%, 70% and 85% improvement. These cutpoints had good face validity concerning the disease activity states achieved by the different response definitions. Construct validity was shown by a clear association of increasing SDAI response categories with increasing levels of functional improvement, achievement of better functional states and lower annual radiographic progression. Across SDAI 50/70/85, the sensitivities regarding a patient-perceived improvement decreased (73%/39%/22%) and the specificities increased (61%/89%/96%) in a meaningful way. Further, the cutpoints discriminated the different treatment arms in ASPIRE and ATTRACT. The same cutpoints were used for the CDAI, with similar results in the validation analyses.

Conclusion

These new response criteria expand the usefulness of the SDAI and CDAI for their use as endpoints in clinical trials beyond the definition of disease activity categories.

Face validity

Clinical disease

10.1136/annrheumdis-2012-201491

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Citations (97)

Circulating tumor cells (CTC) and KRAS mutant circulating free DNA (cfDNA) detection in peripheral blood as biomarkers in patients diagnosed with exocrine pancreatic cancer

BMC Cancer (2015)

Julie Earl Sandra García-Nieto José Carlos Martínez Ávila José Montáns Alfonso Sanjuánbenito

Pancreatic cancer remains one of the most difficult cancers to treat with the poorest prognosis. The key to improving survival rates in this disease is early detection and monitoring of disseminated and residual disease. However, this is hindered due to lack reliable diagnostic and predictive markers which mean that the majority of patients succumb to their condition within a few months.We present a pilot study of the detection circulating free DNA (cfDNA) combined with tumor specific mutation detection by digital PCR as a novel minimally invasive biomarker in pancreatic ductal adenocarcinoma (PDAC). This was compared to the detection of CTC by the CellSearch® system and a novel CTC enrichment strategy based on CD45 positive cell depletion. The aim of the study was to assess tumor specific DNA detection in plasma and CTC detection as prognostic markers in PDAC.We detected KRAS mutant cfDNA in 26% of patients of all stages and this correlated strongly with Overall Survival (OS), 60 days (95% CI: 19-317) for KRAS mutation positive vs 772 days for KRAS mutation negative (95% CI: 416-1127). Although, the presence of CTC detected by the CellSearch® system did correlate significantly with OS, 88 days (95% CI: 27-206) CTC positive vs 393 days CTC negative (95% CI: 284-501), CTC were detected in only 20% of patients, the majority of which had metastatic disease, whereas KRAS mutant cfDNA was detected in patients with both resectable and advanced disease.Tumor specific cfDNA detection and CTC detection are promising markers for the management of patients with PDAC, although there is a need to validate these results in a larger patient cohort and optimize the detection of CTC in PDAC by applying the appropriate markers for their detection.

Circulating tumor cell

Surgical oncology

Liquid biopsy

Minimal Residual Disease

10.1186/s12885-015-1779-7

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Citations (164)

Correction to: Pharmacometabolomics applied to zonisamide pharmacokinetic parameter prediction

Metabolomics (2018)

José Carlos Martínez Ávila Alberto Bartolomé Irene García-García Irene Dapía Hoi Y. Tong

Mistake

Zonisamide

10.1007/s11306-018-1378-0

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Citations (2)