Identifying genomic biomarkers for cancer treatment

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 23-05-2017Esta tesis tiene embargado el acceso al texto completo hasta el 23-11-2018Es bien conocida la existencia de importantes diferencias interindividuales en la respuesta a la mayoría de los medicamentos, pero dicha variabilidad es de especial relevancia en oncología, ya que el cáncer es una de las principales causas de morbilidad y mortalidad y puesto que los antineoplásicos presentan un índice terapéutico muy estrecho. Aunque dicha variabilidad puede ser atribuida a diferentes factores, la variación genética se postula como uno de los factores más importantes. En esta tesis doctoral nos hemos centrado en la identificación de variantes genéticas asociadas a respuesta tumoral, supervivencia y efectos adversos en pacientes oncológicos. A pesar de la eficacia de los tratamientos actuales para el sarcoma de Ewing, el pronóstico para aquellos pacientes con enfermedad metastásica y refractaria es desfavorable. Por tanto, la identificación de variantes genéticas predictivas y pronósticas resulta esencial para optimizar el tratamiento en dichos pacientes. Con este objetivo estudiamos variantes genéticas en aquellos genes implicados en el transporte y metabolismo de los fármacos más comúnmente utilizados en el tratamiento del sarcoma de Ewing e identificamos tres variantes comunes en los genes ABCC6, ABCB1 y CYP2C8 asociadas con la supervivencia de estos pacientes. El síndrome mano-pie es el más común de los afectos adversos producidos por la capecitabina, afectando a más de un 30% de los pacientes. Su aparición conlleva graves consecuencias clínicas ya que obliga a reducir la dosis o incluso a la suspensión del tratamiento. Los marcadores genéticos identificados hasta la fecha se encuentran involucrados en su totalidad en el proceso de biotransformación de la capecitabina y su utilidad predictiva es incierta. La combinación de un estudio de asociación del genoma completo junto con estudios funcionales nos ha permitido la identificación de un locus de susceptibilidad a este efecto adverso. Este locus regula la expresión del gen CDH4, probablemente mediante alteraciones en la topología de la cromatina. Además encontramos que aquellos pacientes que sufren una toxicidad más severa presentan en su piel reducidos niveles de la proteína que codifica CDH4, R-cadherina (altamente expresada en el estrato granuloso de la epidermis) y de involucrina (proteína del estrato cornificado esencial para la función de barrera de la epidermis). El tratamiento con antraciclinas produce efectos cardiotóxicos irreversibles e incluso fatales tanto en niños como en adultos y los factores de riesgo identificados hasta la fecha se han mostrado insuficientes para la estratificación de los pacientes. En esta tesis hemos encontrado nuevas variantes poco frecuentes asociadas a cardiotoxicidad en los genes GPR35 en pacientes oncológicos infantiles, y ETFB y WISP1 independientemente de la edad de diagnóstico. Todos los resultados obtenidos en esta tesis doctoral suponen una clara evidencia del importante papel que juega la variación genética en las diferencias interindividuales observadas tanto en la eficacia como en la toxicidad de los quimioterapéuticos y por tanto, podrían ser utilizados en el futuro en el diseño de una medicina individualizada en estos pacientes

Narcissus dubius, Narcisse Douteux

This species is endemic to southern France and eastern Spain. It is assessed as Least Concern because it has a widespread distribution, occurs in several protected areas throughout its range and its population is not expected to significantly decline in the near future. Further studies on the genetic structure of its population and trends in population size at global level are needed

Juncus fernandez-carvajaliae

This species is endemic to central Spain, where it is currently only known from two sites in the Guadiana River basin located in the western half of Ciudad Real Province. Suitable habitat is frequent around both known sites, and the potential distribution area of this new species could be much larger. However, very little data are available at present regarding its population size, trends or threats and therefore it is assessed as Data Deficient; further research is required

Online psycho-education to the treatment of bipolar disorder: protocol of a randomized controlled trial

Background: Bipolar disorder patients frequently present recurrent episodes and often experience subsyndromal symptoms, cognitive impairment and difficulties in functioning, with a low quality of life, illness relapses and recurrent hospitalization. Early diagnosis and appropriate intervention may play a role in preventing neuroprogression in this disorder. New technologies represent an opportunity to develop standardized psychological treatments using internet-based tools that overcome some of the limitations of face-to-face treatments, in that they are readily accessible and the timing of therapy can be tailored to user needs and availability. However, although many psychological programs are offered through the web and mobile devices for bipolar disorder, there is a lack of high quality evidence concerning their efficacy and effectiveness due to the great variability in measures and methodology used. Methods: This clinical trial is a simple-blind randomized trial within a European project to compare an internet-based intervention with treatment as usual. Bipolar disorder patients are to be included and randomly assigned to one of two groups: 1) the experimental group (tele-care support) and 2) the control group. Participants in both groups will be evaluated at baseline (pre-treatment) and post-treatment. Discussion: This study describes the design of a clinical trial based on psychoeducation intervention that may have a significant impact on both prognosis and treatment in bipolar disorder. Specifically, bringing different services together (service aggregation), it is hoped that the approach proposed will significantly increase the impact of information and communication technologies on access and adherence to treatment, quality of the service, patient safety, patient and professional satisfaction, and quality of life of patients.This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No 604691

Cannabis use and involuntary admission may mediate long-term adherence in first-episode psychosis patients: a prospective longitudinal study

Background: This study aimed to examine factors associated with treatment adherence in first-episode psychosis (FEP) patients followed up over 8 years, especially involuntary first admission and stopping cannabis use. Methods: This prospective, longitudinal study of FEP patients collected data on symptoms, adherence, functioning,and substance use. Adherence to treatment was the main outcome variable and was categorized as ‘good’ or ‘bad’. Cannabis use during follow-up was stratified as continued use, stopped use, and never used. Bivariate and logistic regression models identified factors significantly associated with adherence and changes in adherence over the 8-year follow-up period. Results: Of the 98 FEP patients analyzed at baseline, 57.1% had involuntary first admission, 74.4% bad adherence,and 52% cannabis use. Good adherence at baseline was associated with Global Assessment of Functioning score (p = 0.019), Hamilton Depression Rating Scale score (p = 0.017) and voluntary admission (p < 0.001). Adherence patterns over 8 years included: 43.4% patients always bad, 26.1% always good, 25% improved from bad to good. Among the improved adherence group, 95.7% had involuntary first admission and 38.9% stopped cannabis use. In the subgroup of patients with bad adherence at baseline, involuntary first admission and quitting cannabis use during follow up were associated with improved adherence. Conclusions: The long-term association between treatment adherence and type of first admission and cannabis use in FEP patients suggest targets for intervention to improve clinical outcomes

Integrated treatment of first episode psychosis with online training (e-learning): study protocol for a randomised controlled trial

BackgroundThe integrated treatment of first episode psychosis has been shown to improve functionality and negative symptoms in previous studies. In this paper, we describe a study of integrated treatment (individual psychoeducation complementary to pharmacotherapy) versus treatment as usual, comparing results at baseline with those at 6-month re-assessment (at the end of the study) for these patients, and online training of professionals to provide this complementary treatment, with the following objectives: 1) to compare the efficacy of individual psychoeducation as add-on treatment versus treatment as usual in improving psychotic and mood symptoms; 2) to compare adherence to medication, functioning, insight, social response, quality of life, and brain-derived neurotrophic factor, between both groups; and 3) to analyse the efficacy of online training of psychotherapists.Methods/designThis is a single-blind randomised clinical trial including patients with first episode psychosis from hospitals across Spain, randomly assigned to either a control group with pharmacotherapy and regular sessions with their psychiatrist (treatment as usual) or an intervention group with integrated care including treatment as usual plus a psychoeducational intervention (14 sessions). Training for professionals involved at each participating centre was provided by the coordinating centre (University Hospital of Álava) through video conferences. Patients are evaluated with an extensive battery of tests assessing clinical and sociodemographic characteristics (Positive and Negative Syndrome Scale, State-Trait Anxiety Inventory, Liebowitz Social Anxiety Scale, Hamilton Rating Scale for Depression, Scale to Assess Unawareness of Mental Disorders, Strauss and Carpenter Prognostic Scale, Global Assessment of Functioning Scale, Morisky Green Adherence Scale, Functioning Assessment Short Test, World Health Organization Quality of Life instrument WHOQOL-BREF (an abbreviated version of the WHOQOL-100), and EuroQoL questionnaire), and brain-derived neurotrophic factor levels are measured in peripheral blood at baseline and at 6 months. The statistical analysis, including bivariate analysis, linear and logistic regression models, will be performed using SPSS.DiscussionThis is an innovative study that includes the assessment of an integrated intervention for patients with first episode psychosis provided by professionals who are trained online, potentially making it possible to offer the intervention to more patients.Trial registrationNCT01783457 clinical trials.gov. Date of registration in primary registry 23 January 2013

Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.

OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.This work was supported by the Spanish Association against Cancer (AECC: Asociación Española contra el Cáncer). Human Genotyping lab is a member of CeGen, PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER (Fondo Europeo de Desarrollo Regional). Sara Ruiz-Pinto is a predoctoral fellow supported by the Severo Ochoa Excellence Programme (Project SEV-2011-0191)

Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients.

PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson